Systematic review and estimated cost-efficacy of biologics compared with narrowband ultraviolet B light for the treatment of moderate to severe psoriasis and atopic dermatitis.

Psoriasis and atopic dermatitis are chronic inflammatory skin conditions, each affecting about 2-3% of the United States adult population. Phototherapy, such as narrowband ultraviolet-B (NB-UVB) therapy have been employed for the treatment of both psoriasis and atopic dermatitis for decades. More recently, systemic biologics have been approved by the Food and Drug Administration (FDA), representing a great advancement in dermatology. No comprehensive study to date has compared the cost efficacy of phototherapy compared to FDA-approved biologics for the treatment of psoriasis and atopic dermatitis. We pursued a systematic review of the literature for studies assessing efficacy of NB-UVB or biologics with endpoints including the Psoriasis Area and Severity Index (PASI) and the Eczema Area and Severity Index (EASI). Thirty-four studies including 55 treatment regimens and 5,123 patients were included in the analysis. Phototherapy costs were estimated with Medicare fee schedules for phototherapy-related current procedural terminology code (CPT), and biologic costs were estimated with wholesale acquisition cost (WAC). Total costs to achieve PASI 75 or EASI 75 in each study were standardized to a single month, the "adjusted cost," and exploited to a year, the "effective yearly cost," allowing direct cost-efficacy comparison despite different durations of treatment described in studies. The psoriasis analysis found NB-UVB to be the most cost-effective therapy, with an adjusted monthly cost of $1714.00 per PASI 75. Infliximab was the least expensive biologic, with an adjusted monthly cost of $2076.00 to $2502.00 per PASI 75. For atopic dermatitis, no NB-UVB studies utilized EASI 75 as their outcome measure, hindering the ability to directly compare cost effectiveness for the treatment of atopic dermatitis. However, all NB-UVB studies depicted a reduced treatment cost per treatment period compared to studies assessing biologics, although this comparison does not account for efficacy. The results depict NB-UVB to be the most cost effective for the treatment of psoriasis and the least expensive per treatment period for the treatment of atopic dermatitis. However, certain factors need to be taken into account. Biologics may be more effective for more severe disease, do not require multiple weekly clinic visits, and the ease for patient compliance may lead some to favor biologic therapy. This study is necessary to allow physicians, patients, and health systems to make informed decisions regarding cost-efficacy for a variety of treatment options.

Assessment of efficacy and safety of UV-based therapy for psoriasis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have proven that ultraviolet (UV)-based phototherapy, including UVB or psoralen UVA (PUVA), and their combination therapies, is effective for psoriasis treatment. OBJECTIVE: To compare the clinical efficacy and adverse events (AEs) of different UV-based phototherapy in psoriasis. METHODS: PubMed, Cochrane Library, Scopus and Embase were systematically searched. A random-effect model network meta-analysis with frequentist framework was performed, and results were reported as risk ratios (RRs) with 95% CI. The main variable for assessing effectiveness and safety are PASI 75 response and withdrawal due to AEs. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA). RESULTS: Thirty-two studies involving a total of 2120 psoriasis patients were included in this network meta-analysis. Overall, no significant difference was reported with respect to withdrawal due to AEs or incidence of erythema. The relatively safest strategy was combined adjuvant therapy with PUVA (cPUVA), especially PUVA combined with calcium/vitamin D derivatives (RR 0.98, 95% CI [0.30-3.17], SUCRA = 80.8%). Both cPUVA (RR 1.39, 95% CI [1.00- 1.94]) and combined adjuvant therapy with UVB (cUVB) (RR 1.27, 95% CI [1.03-1.57]) showed a superior effect than the monotherapy of UVA or UVB, respectively. PUVA combined with vitamin D and its derivatives (PAVD) ranked highest concerning clinical effect and safety (clusterank value = 7393.2). CONCLUSIONS: The efficacy of all the combination therapy regimens was significantly superior to that of UV monotherapy, without significant differences in tolerability and safety. cUVB and cPUVA, and particularly the combination of UVA with calcium/vitamin D derivatives, was ranked as the overall safest and most effective phototherapy method.

Efficacy assessment of UVA1 and narrowband UVB for treatment of scalp psoriasis.

To compare the efficacy and safety of UVA1 and narrowband UVB (NB-UVB) therapy in the treatment of scalp psoriasis. Patients with scalp psoriasis were randomly assigned to either UVA1 or NB-UVB therapy. Both treatments were performed three times weekly for 6 weeks. Clinical efficacy was evaluated by using Psoriasis Scalp Severity Index (PSSI), and patient-reported quality of life (QoL) was assessed by Dermatology Life Quality Index (DLQI). Totally 68 patients completed the study. Both UVA1 and NB-UVB phototherapy achieved a statistically significant reduction of PSSI and DLQI scores at the end of the treatment period. Compared with the NB-UVB group, the significantly greater improvements occurred in UVA1 treatment group at week 3, although differences declined thereafter through week 10. Both UVA1 and NB-UVB therapy were well-tolerated in this study, and the occurrence of adverse events (AEs) was uncommon. Both UVA1 and NB-UVB phototherapy could offer relief of scalp symptoms in patients with scalp involvement. Furthermore, UVA1 treatment could improve the clinical manifestations and QoL more quickly than NB-UVB therapy.

Narrowband ultraviolet B treatment for psoriasis is highly economical and causes significant savings in cost for topical treatments.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) treatment for psoriasis is considered expensive. However, existing data are based on estimates and do not consider indirect cost savings. OBJECTIVES: To define the actual costs of NB-UVB incurred by the service provider, as well as treatment-associated cost savings. METHODS: We performed data linkage of (i) comprehensive treatment records and (ii) prescribing data for all NB-UVB treatment episodes spanning 6 years in a population of 420 000. We minimized data fluctuation by compiling data from four independent treatment sites, and using drug prescriptions unrelated to psoriasis as a negative control. RESULTS: National Health Service Tayside spent an average of £257 per NB-UVB treatment course (mean 257 ± 63, range 150-286, across four independent treatment sites), contrasting sharply with the estimate of £1882 used by the U.K. National Institute for Health and Care Excellence. The cost of topical treatments averaged £128 per patient in the 12 months prior to NB-UVB, accounting for 42% of the overall drug costs incurred by these patients. This was reduced by 40% to £53 per patient over the 12-month period following NB-UVB treatment, while psoriasis-unrelated drug prescription remained unchanged, suggesting disease-specific effects of NB-UVB. The data were not due to site-specific factors, as confirmed by highly similar results observed between treatment sites operated by distinct staff. Finally, we detail all staff hours directly and indirectly involved in treatment, allowing direct translation of cost into other healthcare systems. CONCLUSIONS: NB-UVB is a low-cost treatment; cost figures currently used in health technology appraisals are an overestimate based on the data presented here. Creating or extending access to NB-UVB is likely to offer additional savings by delaying or avoiding costly third-line treatments for many patients.

A Systematic Review of Light Emitting Diode (LED) Phototherapy for Treatment of Psoriasis: An Emerging Therapeutic Modality.

Background: Psoriasis is a chronic, inflammatory skin condition. The economic burden of psoriasis is approximately $35.2 billion in the United States per year, and treatment costs are increasing at a higher rate than general inflation. Light emitting diode (LED) phototherapy may represent a cost-effective, efficacious, safe, and portable treatment modality for psoriasis.

Objective: The goal of our manuscript is to review the published literature and provide evidence-based recommendations on LED phototherapy for the treatment of psoriasis.

Methods & Materials: A search of the databases Pubmed, EMBASE, Web of Science, and CINAHL was performed on April 5, 2016. Key search terms were related to psoriasis and LED-based therapies.

Results: A total of 7,793 articles were generated from the initial search and 5 original articles met inclusion criteria for our review. Grade of recommendation: B for LED-blue light. Grade of recommendation: C for LED-ultraviolet B, LED-red light, and combination LED-near-infrared and LED-red light.

Conclusion: We envision further characterizing the effects of LED phototherapy to treat psoriasis in patients may increase adoption of LED-based modalities and provide clinicians and patients with new therapeutic options that balance safety, efficacy, and cost.

J Drugs Dermatol. 2017;16(5):482-488.

Malignancy rates in a large cohort of patients with systemically treated psoriasis in a managed care population.

BACKGROUND: Moderate to severe psoriasis often requires treatment with systemic agents, many of which have immunosuppressive properties and could increase cancer risk, including nonmelanoma skin cancer (NMSC). OBJECTIVE: We sought to estimate the overall malignancy rate (excluding NMSC) and NMSC rate among 5889 patients with systemically treated psoriasis. METHODS: We identified a cohort of adult Kaiser Permanente Northern California health plan members with psoriasis diagnosed from 1998 to 2011 and treated with at least 1 systemic antipsoriatic agent and categorized them into ever-biologic or nonbiologic users. Malignancy rates were calculated per 1000 person-years of follow-up with 95% confidence intervals (CI). Crude and confounder-adjusted hazard ratios (aHRs) were calculated using Cox regression. RESULTS: Most biologic-exposed members were treated with TNF-alfa inhibitors (n = 2214, 97%). Overall incident cancer rates were comparable between ever-biologic as compared to nonbiologic users (aHR 0.86, 95% CI 0.66-1.13). NMSC rates were 42% higher among individuals ever exposed to a biologic (aHR 1.42, 95% CI 1.12-1.80), largely driven by increased cutaneous squamous cell carcinoma risk (aHR 1.81, 95% CI 1.23-2.67). LIMITATIONS: No information was available on disease severity. CONCLUSION: We found increased incidence of cutaneous squamous cell carcinoma among patients with systemically treated psoriasis who were ever exposed to biologics, the majority of which were TNF-alfa inhibitors. Increased skin cancer surveillance in this population may be warranted.

Phototherapy with Narrow-Band UVB in Adult Guttate Psoriasis: Results and Patient Assessment.

BACKGROUND: Acute guttate psoriasis (AGP) is a distinctive clinical entity with good response to treatment with narrow-band ultraviolet B (NB-UVB). OBJECTIVE: To investigate the results of NB-UVB phototherapy in adult patients with adult guttate psoriasis. MATERIAL AND METHODS: We carried out a prospective, open, and observational study. Patients over 18 years with more than 5% of body surface area affected were included. The PASI was assessed prior to and after treatment. The follow-up period was 18 months. After treatment, patients completed a simple questionnaire to assess their overall impression of the treatment. RESULTS: The 67 adult patients with AGP included in this study had an initial PASI of 8.55 (SD 5.03). Patients were treated with a mean of 19.9 sessions (SD 13.5) and mean doses of 14 mJ/cm2 (SD 10.5). Of the 67 patients, 52 achieved PASI90 with 96.15% of PASI reduction, and of these, 46 (88%) maintained PASI90 during the 18 months of follow-up. Patients were very satisfied with the treatment. DISCUSSION: AGP is a defined clinical entity with a variable course. Phototherapy with NB-UVB appears to be a very good option for treatment of AGP because of the good results obtained and patient satisfaction.

Estimated cost efficacy of systemic treatments that are approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis.

BACKGROUND: Newer psoriasis treatments tout higher efficacy but are generally more expensive. OBJECTIVE: We sought to estimate the cost efficacy of systemic psoriasis treatments that have been approved by the US Food and Drug Administration (FDA). METHODS: A literature review of systemic psoriasis treatments that have been approved by the FDA was performed for the primary end point of a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75). Medication cost was referenced by wholesale acquisition cost (WAC), laboratory fees were obtained from the American Medical Association, and office visit fees are standard at our university. Total expenses were standardized by calculating cost per month of treatment considering the number needed to treat (NNT) to achieve PASI 75. RESULTS: Methotrexate ($794.05-1502.51) and cyclosporine ($1410.14-1843.55) had the lowest monthly costs per NNT to achieve PASI 75. The most costly therapies were infliximab ($8704.68-15,235.52) and ustekinumab 90 mg ($12,505.26-14,256.75). Monthly costs per NNT to achieve PASI 75 for other therapies were as follows: narrowband ultraviolet B light phototherapy ($2924.73), adalimumab ($3974.61-7678.78), acitretin ($4137.71-14,148.53), ustekinumab 45 mg ($7177.89-7263.99), psoralen plus ultraviolet A light phototherapy ($7499.46-8834.98), and etanercept ($8284.71-10,674.89). LIMITATIONS: Drug rebates and incentives, potential adverse effects, comorbidity risk reduction, ambassador programs, and combination therapies were excluded. CONCLUSION: Our study provides meaningful cost efficacy data that may influence psoriasis treatment selection.

Phototherapy and photochemotherapy for psoriasis.

Phototherapy is a first-line option for the treatment of moderate to severe psoriasis. Systematic reviews indicate near comparable efficacy of the different forms of phototherapy. Localized phototherapy can be an adjunctive treatment of recalcitrant plaques during systemic treatment of psoriasis. More than 200 psoralen-UV-A therapy treatment sessions is associated with an increased risk of keratinocytic cancers, whereas no increased risk has been demonstrated for narrow-band UV-B therapy. The mechanism of action of phototherapy in psoriasis is via inhibition of keratinocyte proliferation; induction of apoptosis in keratinocytes, dendritic, and T cells; and inhibition of Th1 and Th17 pathways, but activation of Th2.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Patient-reported reasons for the discontinuation of commonly used treatments for moderate to severe psoriasis.

BACKGROUND: Despite widespread dissatisfaction and low treatment persistence in moderate to severe psoriasis, patients' reasons behind treatment discontinuation remain poorly understood. OBJECTIVES: We sought to characterize patient-reported reasons for discontinuing commonly used treatments for moderate to severe psoriasis in real-world clinical practice. METHODS: A total of 1095 patients with moderate to severe plaque psoriasis from 10 dermatology practices who received systemic treatments completed a structured interview. Eleven reasons for treatment discontinuation were assessed for all past treatments. RESULTS: A total of 2231 past treatments were reported. Median treatment duration varied by treatment, ranging from 6.0 to 20.5 months (P < .001). The frequency of each cited discontinuation reasons differed by treatment (all P < .01). Patients who received etanercept (odds ratio [OR] 5.19; 95% confidence interval [CI] 3.23-8.33) and adalimumab (OR 2.10; 95% CI 1.20-3.67) were more likely to cite a loss of efficacy than those who received methotrexate. Patients who received etanercept (OR 0.34; 95% CI 0.23-0.49), adalimumab (OR 0.48; 95% CI 0.30-0.75), and ultraviolet B phototherapy (OR 0.21; 95% CI 0.14-0.31) were less likely to cite side effects than those who received methotrexate, whereas those who received acitretin (OR 1.56; 95% CI 1.08-2.25) were more likely to do so. Patients who underwent ultraviolet B phototherapy were more likely to cite an inability to afford treatment (OR 7.03; 95% CI 3.14-15.72). LIMITATIONS: The study is limited by its reliance on patient recall. CONCLUSIONS: Different patterns of treatment discontinuation reasons are important to consider when developing public policy and evidence-based treatment approaches to improve successful long-term psoriasis control.

[Analysis of the cost effectiveness of home-based phototherapy with narrow-band UV-B radiation compared with biological drugs for the treatment of moderate to severe psoriasis]. / Análisis coste-efectividad de la fototerapia domiciliaria con ultravioleta B de banda estrecha frente a fármacos biológicos en el tratamiento de la psoriasis moderada-grave.

BACKGROUND: Psoriasis is associated with high treatment costs due to the increasing use of biologic drugs. Phototherapy has been demonstrated to be safe and cost effective for the treatment of psoriasis, although it is limited by the requirement for patients to visit a hospital various times a week. OBJECTIVES: To evaluate the efficiency of home-based phototherapy with narrow-band UV-B radiation compared with biologic drugs for the treatment of moderate to severe psoriasis under normal practice conditions in our setting. METHODS: A retrospective cost-effectiveness study was undertaken in 12 patients with moderate to severe psoriasis. Half of the patients were treated with biologic drugs (2 with etanercept, 2 with adalimumab, and 2 with infliximab) and the other half with home-based phototherapy using a Waldmann UV100L-TL01 lamp. Clinical effectiveness was determined on the basis of achieving a 75% improvement in Psoriasis Area and Severity Index (PASI 75) within 16 weeks of treatment. RESULTS: Treatment was considered to be effective in 5 out of 6 patients (83%) treated with biologics and 4 out of 6 patients (66%) treated with home-based phototherapy. The direct costs required to achieve PASI 75 were 8256€ per patient for biologics and 903€ per patient for home-based phototherapy. The costs associated with effective treatment using biologic drugs in a single patient would provide effective home-based phototherapy for 9.1 patients. LIMITATIONS: The study included a limited number of patients analyzed over a short time period (16 weeks) and the comparison group included multiple treatments with different predicted responses. CONCLUSIONS: Although biologic drugs exhibited greater efficacy, home-based phototherapy was more efficient for the treatment of moderate to severe psoriasis. Home-based phototherapy represents a cost-effective treatment option for patients with psoriasis and may be appropriate for use in the Spanish health care system.

Trends in home phototherapy adoption in the US: monetary disincentives are only the tip of the iceberg.

There are often multiple hurdles that must be crossed to obtain home phototherapy devices. To identify these obstacles, we examined survey data from the National Biological Corporation on patients who never acquired a home unit after being given a prescription from their doctors. Additionally, physicians' prescribing patterns were assessed from data gathered by IMS Health. Physician education of and willingness to prescribe home phototherapy was assessed via a survey distributed at the 9th Annual Dermatology Chief Residents' Meeting. When psoriasis patients were written a prescription for home phototherapy, less than half acquired a unit. Most patients (72%) stated that they did not get a unit secondarily to the high out-of-pocket expenses. In 2006, dermatologists wrote 94,385 new scripts for etanercept, compared with only 1073 scripts for home phototherapy. Very few (35%) dermatology residents receive formal training on home phototherapy. When it comes to the reasons behind patients receiving significantly more expensive biologics instead of home phototherapy for their psoriasis, high copays and deductibles are just the tip of the iceberg. It is likely that even more patients are never prescribed a home unit due to lack of physician training or frustration with meager and often inadequate reimbursements from insurance.

Cost effectiveness of home ultraviolet B phototherapy for psoriasis: economic evaluation of a randomised controlled trial (PLUTO study).

OBJECTIVE: To assess the costs and cost effectiveness of phototherapy with ultraviolet B light provided at home compared with outpatient ultraviolet B phototherapy for psoriasis. DESIGN: Cost utility, cost effectiveness, and cost minimisation analyses performed alongside a pragmatic randomised clinical trial (the PLUTO study) at the end of phototherapy (mean 17.6 weeks) and at one year after the end of phototherapy (mean 68.4 weeks). SETTING: Secondary care, provided by a dermatologist in the Netherlands. PARTICIPANTS: 196 adults with psoriasis who were clinically eligible for narrowband (TL-01) ultraviolet B phototherapy were recruited from the dermatology departments of 14 hospitals and were followed until the end of phototherapy. From the end of phototherapy onwards, follow-up was continued for an unselected, consecutive group of 105 patients for one year after end of phototherapy. INTERVENTIONS: Ultraviolet B phototherapy provided at home (intervention) and conventional outpatient ultraviolet B phototherapy (control) in a setting reflecting routine practice in the Netherlands. Both treatments used narrowband ultraviolet B lamps (TL-01). MAIN OUTCOME MEASURES: Total costs to society, quality adjusted life years (QALYs) as calculated using utilities measured by the EQ-5D questionnaire, and the number of days with a relevant treatment effect (>/=50% improvement of the baseline self administered psoriasis area and severity index (SAPASI)). RESULTS: Home phototherapy is at least as effective and safe as outpatient phototherapy, therefore allowing cost minimisation analyses (simply comparing costs). The average total costs by the end of phototherapy were euro800 for home treatment and euro752 for outpatient treatment, showing an incremental cost per patient of euro48 (95% CI euro-77 to euro174). The average total costs by one year after the end of phototherapy were euro1272 and euro1148 respectively (difference euro124, 95% CI euro-155 to euro403). Cost utility analyses revealed that patients experienced equal health benefits-that is, a gain of 0.296 versus 0.291 QALY (home v outpatient) by the end of phototherapy (difference 0.0052, -0.0244 to 0.0348) and 1.153 versus 1.126 QALY by one year after the end of phototherapy (difference 0.0267, -0.024 to 0.078). Incremental costs per QALY gained were euro9276 and euro4646 respectively, both amounts well below the normally accepted standard of euro20 000 per QALY. Cost effectiveness analyses indicated that the mean number of days with a relevant treatment effect was 42.4 versus 55.3 by the end of phototherapy (difference -12.9, -23.4 to -2.4). By one year after the end of phototherapy the number of days with a relevant treatment effect were 216.5 and 210.4 respectively (6.1, -41.1 to 53.2), yielding an incremental cost of euro20 per additional day with a relevant treatment effect. CONCLUSIONS: Home ultraviolet B phototherapy for psoriasis is not more expensive than phototherapy in an outpatient setting and proved to be cost effective. As both treatments are at least equally effective and patients express a preference for home treatment, the authors conclude that home phototherapy should be the primary treatment option for patients who are eligible for phototherapy with ultraviolet B light. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83025173 and Clinicaltrials.gov NCT00150930.

Paradoxical effects of cost reduction measures in managed care systems for treatment of severe psoriasis.

BACKGROUND: Insurance companies vary widely in their coverage policies for severe psoriasis therapies. Unfortunately, coverage policies for psoriasis therapies do not necessarily follow current treatment paradigms, such that more expensive second or third line treatments may be more easily obtained than first line treatments. METHODS: We reviewed insurance policy bulletins, statements of coverage/medical necessity, and prior authorization forms for three large insurance carriers regarding psoriasis treatment with biologic agents and phototherapy. A cost comparison was performed to estimate total costs to patients and insurer under the current system as well as a hypothetical system in which co-pays and deductibles are eliminated. Additionally, we reviewed the total cost to an insurer for placing a patient on a trial of home phototherapy before approving use of expensive biologics. RESULTS: Requirements for coverage for phototherapy treatments are often the same, if not more stringent, than those for biologics. On an annual per patient basis, insurance companies pay an estimated $5, $76, and $23,408 for home phototherapy, office phototherapy, and biologics, respectively. The first year cost to patients, however, is estimated to be $2,590, $3,040, and $920 for home phototherapy, office phototherapy, and biologics, respectively. An initial 3-month trial of home phototherapy yields a graded annual cost savings to insurers of $21,610 to $2,110 per patient. DISCUSSION: The evolution of psoriasis treatment has resulted in a paradoxical situation in which the use of lower-cost psoriasis treatments, with longer safety track records, is discouraged relative to newer options. If co-pays, deductibles, and prior authorization requirements that discourage phototherapy were reduced or eliminated, more patients and physicians would likely choose phototherapy over biologics. This has the potential to reduce overall healthcare costs for psoriasis management.

Patients with moderate-to-severe plaque psoriasis preferred oral therapies to phototherapies: a preference assessment based on clinical scenarios with trade-off questions.

OBJECTIVE: The importance of validly identifying and incorporating patients' views for improving health care is generally acknowledged. Common approaches to assess patients' preferences are based on the quality adjusted life year (QALY) framework, but this ignores a number of aspects that may be relevant. As an alternative, we assessed patients' treatment preferences and trade-offs for five common systemic therapies for psoriasis. STUDY DESIGN AND SETTING: Twenty-nine patients with moderate-to-severe psoriasis expressed treatment preferences for five oral and phototherapies and indicated the relative importance of various treatment attributes, such as adverse effects, discomforts, and safety measures. In a structured interview, they were presented with clinical scenarios that contained descriptions of process and outcome characteristics and illustrations of the anticipated treatment benefit. RESULTS: Over all paired comparisons, methotrexate (33%), cyclosporin (30%), acitretin (15%), UV-B (14%), and PUVA (8%) were preferred to the other treatment. Patients were willing to trade-off their initial preference for more improvement of psoriasis. CONCLUSIONS: Psoriasis patients generally prefer oral to phototherapies and consider most adverse effects and several discomforts important for selecting treatment. Our scenario-based structured interview approach to treatment preferences allowed us to incorporate a broad spectrum of potentially relevant decision components in a clinically meaningful way.