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Effectiveness outcomes in trials of mitoxantrone compared with 92 placebo Outcome Time point Number Results a 68 purchase ondansetron 8mg on line symptoms 12 dpo. Disease-modifying drugs for multiple sclerosis Page 45 of 120 Final Report Update 1 Drug Effectiveness Review Project Mixed populations: Primary and secondary progressive multiple sclerosis Glatiramer acetate ® An early buy discount ondansetron 4mg on line hb treatment, good-quality study of glatiramer acetate (Copaxone ) was conducted in a population of 106 patients described as chronic progressive (a chronic progressive course for at least 18 months cheap ondansetron 8mg mastercard treatment impetigo, no more than 2 exacerbations in the past 2 years purchase ondansetron australia symptoms 3 dpo, Expanded Disability Status Scale ≥2 97 and ≤6. Many clinicians consider this group of patients to represent a mix of patients with what would now be called primary or secondary progressive multiple sclerosis. The drug used in this study was available from 2 laboratories in Israel and was not the commercially available glatiramer acetate (known as COP-1 at the time). The dosing of the drug was 15 mg subcutaneously twice daily, a dose that is higher than currently used (20 mg subcutaneously daily). The mean baseline Expanded Disability Status Scale was slightly higher in the glatiramer acetate group (5. Comparing time to sustained progression curves (the primary outcome) while the glatiramer acetate curve showed slower progression, no significant difference was found between the groups over a 2-year period. This study did not conduct a sample size calculation, and with 106 patients may have been underpowered to show a difference of this magnitude. Further, subgroup analyses indicated that patients enrolled at the 2 centers responded differently while on study, and that overall patient disease activity differed on trial compared with the pre-trial assessment period. Analysis of secondary outcomes indicated that statistically significant differences in proportions with progression (defined as an increase on Expanded Disability Status Scale of ≥ 1 if baseline ≥ 5, and 1. The authors also explored a definition of progression of an increase of only 0. Using this definition, the probability of progression was significantly lower with glatiramer acetate compared with placebo only at the 24-month time point (44. Do disease-modifying treatments for multiple sclerosis differ in their effects on the development or recurrence of interferon beta neutralizing antibodies? Summary of the Evidence ® • Interferon beta-1a IM (Avonex ) appeared to have the lowest immunogenicity, with rates of development of neutralizing antibodies of 2% to 8. Disease-modifying drugs for multiple sclerosis Page 46 of 120 Final Report Update 1 Drug Effectiveness Review Project Detailed Assessment Neutralizing antibodies are known to develop in some patients taking beta interferons, potentially interfering with effectiveness. Two systematic reviews summarized the current state of understanding about the impact 98, 99 of these antibodies on relapse and disease progression, and how the products differ. There were several factors that can impact the prevalence of such antibodies, including assay method (varying sensitivity/specificity), dose (conflicting evidence), host cell source (Escherichia coli more antigenic than mammalian source), definition of positive status, and route of administration (subcutaneous more antigenic than intramuscular). Because there is no standardized universal assay, comparisons across studies of the beta interferons is fraught with uncertainty. It appears that the rate of antibody development occurs earlier and in greater frequency with interferon ® beta-1b SC (Betaseron ), appearing as early as 3 months into treatment in approximately 30% to 99 40% of patients. Evidence reported in the Namaka review indicated that antibodies occur ® somewhat later (9 months) with interferon beta-1a SC (Rebif ), with rates as low as 12% and as ® high as 46% (see Table 18). Interferon beta-1a IM (Avonex ) appeared to have the lowest immunogenicity with rates of 2% to 8. Importantly, 40% to 50% of antibody-positive patients will become antibody-negative over time, while small numbers of patients will become antibody-positive into the second year of treatment. Comparison of neutralizing antibodies in beta interferon products Avonex Betaseron Rebif Percent developing neutralizing 2% to 6% 30% to 40% 12% to 25% antibodies First 3-6 months, can Time to appear First 9-15 months First 9-15 months occur up to month 18 Data from 9 comparative observational studies reporting the presence of neutralizing 100-108 antibodies in patients taking beta interferons are shown in Table 19 below. The proportion ® of patients developing antibodies was lower for interferon beta-1a IM (Avonex ), 0% to 14%, ® compared with 11% to 44% with interferon beta-1a SC (Rebif ) and 15% to 44% with interferon ® beta-1b SC (Betaseron ), consistent with findings from the Namaka systematic review. The usefulness of these studies in making comparisons across drugs was limited because most did not study patients on therapy for more than 2 years. Disease-modifying drugs for multiple sclerosis Page 47 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 19. Proportion of patients testing neutralizing antibody-positive after beta interferon therapy reported in comparative observational studies Association of clinical Author, Duration of outcomes with neutralizing ® ® ® year treatment Avonex Betaseron Rebif antibody status More relapses in neutralizing 16/131 Boz, 2007 >3 years 0/12 (0%) 18/119 (15%) antibody-positive patients in (12. Relapse rates higher in Farrell, 24/292 neutralizing antibody-positive >3 years 4/242 (6%) 11/115 (28%) 2008 (30%) groups, risk greater in those with higher titres Median 26 No significant association Dubois, 10/23 months, range 0/18 (0%) 12/32 (38%) between antibody status and 2006 (44%) 2-85 months outcomes. Kivisakk, No effect of neutralizing 1-46 months 1/20 (5%) 21/48 (44%) 2000 antibodies on clinical outcome Koch- 21,963 Effect of neutralizing antibody N=417 N=892 Henriksen months of status on relapses did not differ 33. They are not discussed in detail here because 80, 107, they provided no additional evidence beyond the Namaka and Goodin systematic reviews. What is the evidence that interferon beta neutralizing antibody status has an impact on clinical outcomes (relapse and disease progression) in patients with multiple sclerosis? Summary of the Evidence ® ® • Evidence for interferon beta-1b SC (Betaseron ) and interferon beta-1a SC (Rebif ) indicated that consistent positive neutralizing antibody status with high titer adversely affected the impact of these drugs on relapse rates, by one-half to two-thirds, during longer periods of follow-up. Detailed Assessment The duration of many studies was not adequate to assess the impact of antibody status on progression clearly. Namaka et al found that in the first 2 years of treatment a difference in outcome based on antibody status could not be identified, but that relapse rates were lower in years 3 and 4 among patients who were antibody-positive (Table 20). The review by Goodin et 98 al also found that relapse rates were affected by positive neutralizing antibody status of high titer only in studies of 2 years or longer in duration. The evidence for the impact on disease progression was less compelling, with only 2 of 8 studies showing a significant increase in progression among those with neutralizing antibodies. Duration of treatment and clinical impact of antibody status Interferon β-1b SC Interferon β-1a SC ® ® ® Duration (Betaseron ) (Rebif ) Interferon β-1a IM (Avonex ) nd “correlation not 1. Two trials published subsequent to the Goodin and Namaka systematic reviews reported rates of interferon beta neutralizing antibodies occurring in enrolled patients. Most of these may not have been of sufficient duration to show clinical effects of antibody development, however. In the EVIDENCE trial, which compared interferon high-dose, high-frequency interferon beta-1a ® ® (Rebif ) 44 mcg to low-dose interferon beta-1a IM (Avonex ) 30 mcg over 2 years, neutralizing ® antibodies were detected at least once in 26% of patients receiving high-dose Rebif and in 3% ® of those receiving low dose Avonex (P<0. Neutralizing antibodies developed earlier with high-dose treatment (58% by week 24, compared with 14% in the low-dose group). Relapse rates 45 were similar in antibody-positive and antibody-negative patients. The proportion of patients developing neutralizing antibodies was reported in the ® REGARD study of interferon beta-1a (Rebif ). The rate was 60/138 (16%) at 24 weeks, 93/355 Disease-modifying drugs for multiple sclerosis Page 49 of 120 Final Report Update 1 Drug Effectiveness Review Project (26%) at 48 weeks, 91/319 (29%) at 72 weeks, and 102/374 (27%) at 96 weeks or last observation carried forward. Neutralizing antibodies had no effect on clinical efficacy: there was no difference in time to first relapse for those positive at any time and those negative (hazard ratio, 1. Although there was an association between neutralizing antibody status and clinical outcome shown in several studies, none found the detrimental effect of positive antibody status to be greater with one of the beta interferons than another. The conclusions that could be drawn from these studies were limited for several reasons: most were not of sufficient duration to show an effect of neutralizing antibodies on clinical status, the numbers of patients taking each drug may not have been sufficient to show a difference between treatments, and lack of control for confounding factors limited the validity of their results. Evidence correlating comparative clinical outcomes to the antibody status of the individual beta interferons was incomplete and inadequate to make conclusions. Longer-term trials will be needed to clarify the role of this difference in antigenicity and its correlation of clinical outcomes over longer periods of time.
For example order 4 mg ondansetron overnight delivery medicine 95a, testing whether one treatment is different than another (rather than testing whether one treatment is either better than another) generic ondansetron 8mg line medicine app. Type I error: A conclusion that there is evidence that a treatment works buy ondansetron 4mg low cost hb treatment, when it actually does not work (false-positive) order genuine ondansetron line medications hard on liver. Type II error: A conclusion that there is no evidence that a treatment works, when it actually does work (false-negative). Validity: The degree to which a result (of a measurement or study) is likely to be true and free of bias (systematic errors). Variable: A measurable attribute that varies over time or between individuals. Variables can be • Discrete: taking values from a finite set of possible values (e. Washout period: [In a crossover trial] The stage after the first treatment is withdrawn, but before the second treatment is started. The washout period aims to allow time for any active effects of the first treatment to wear off before the new one gets started. Attention deficit hyperactivity disorder 160 of 200 Final Update 4 Report Drug Effectiveness Review Project Appendix B. Boxed warnings of ADHD drugs Trade name Active ingredient(s) Boxed warnings Amphetamine mixture (amphetamine aspartate; amphetamine ® sulphate; Adderall XR Amphetamines have a high potential for abuse. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is ® required during withdrawal from abusive use since severe Focalin and Dexmethylphenidate ® depression may occur. Withdrawal following chronic Focalin XR hydrochloride therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. It should be tried only in weight reduction programs for patients in whom alternative therapy has been ineffective. Administration of methamphetamine for prolonged periods of time in obesity may lead to drug dependence and must ® Methamphetamine Desoxyn be avoided. Particular attention should be paid to the hydrochloride possibility of subjects obtaining methamphetamine for non- therapeutic use or distribution to others, and the drugs should be prescribed or dispensed sparingly. Misuse of methamphetamine may cause sudden death and may lead to serious cardiovascular events. Chronically abusive use can lead to marked tolerance and ® Methylphenidate psychic dependence with varying degrees of abnormal Methylin hydrochloride behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked. Long- term follow-up may be required because of the patient’s basic personality disturbances. Attention deficit hyperactivity disorder 161 of 200 Final Update 4 Report Drug Effectiveness Review Project Trade name Active ingredient(s) Boxed warnings WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS ® Strattera (atomoxetine) increased the risk of suicidal ideation in short-term studies in children or adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Co- morbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior. Patients who are started on therapy should be monitored closely for suicidality (suicidal thinking and behavior), clinical worsening, or unusual changes in behavior. Families and caregivers should be advised of the need for ® Atomoxetine Strattera close observation and communication with the prescriber. Hydrochloride ® Strattera is approved for ADHD in pediatric and adult ® patients. Strattera is not approved for major depressive disorder. Pooled analyses of short-term (6 to 18 weeks) placebo- ® controlled trials of Strattera in children and adolescents (a total of 12 trials involving over 2200 patients, including 11 trials in ADHD and 1 trial in enuresis) have revealed a greater risk of suicidal ideation early during treatment in ® those receiving Strattera compared to placebo. The average risk of suicidal ideation in patients receiving ® Strattera was 0. Attention deficit hyperactivity disorder 162 of 200 Final Update 4 Report Drug Effectiveness Review Project 6. Attention deficit hyperactivity disorder 163 of 200 Final Update 4 Report Drug Effectiveness Review Project Appendix C. Scales used to assess efficacy and adverse events The following narrative briefly describes the most commonly used assessment scales and summarizes methods of scoring and validation. Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, ICFs/MR, and work training centers. It is also useful for classifying problem behaviors of children and adolescents with mental retardation in educational settings, residential and community-based facilities, and developmental centers. Then 58 specific symptoms are rated and an extensive manual gives comprehensive descriptions for each assessed behavior. The checklist can be completed by parents, special educators, psychologists, direct caregivers, nurses, and others with knowledge of the person being assessed. Extensive psychometric assessment of the ABC has indicated that its subscales have high internal consistency, adequate reliability, and established validity. Average subscale scores are available for both United States and overseas residential facilities and for children and adults 1 living in the community. ADHD Behavior Checklist/ADHD Rating Scale evaluates inattentive and hyperactive-impulsive symptoms, is based on DSM criteria for diagnosing ADHD. DSM-III uses a 14-item checklist while DSM-IV updated it to an 18-item checklist with two nine-item subscales. Items are rated for severity from zero to three according to how often the symptoms are present (0=never/rarely, 1=sometimes, 2=often, and 3=very often). The maximum scores are 42 points and 54 points for DSM-III and DSM-IV respectively. The content validity and construct validity were proved as well. The checklist has established validity, reliability, and age-matched cut-off values 2, 3 ADHDRS- IV or ADHD rating scale IV: an 18-item scale based on a semistructured interview with the patient’s parent by the investigator to assess symptom severity. Each item, corresponding to one of the 18 DSM-IV diagnostic criteria, is rated on a 4-point scale (0 =never or rarely; 1 = sometimes; 2 =often; 3 = very often). This scale has been shown to be a reliable 4 and valid instrument of ADHD symptom severity. The ADHDRS-IV-PI is an 18-item scale assessing ADHD symptoms over the past week based on clinician interviews with patients and parents. Items correspond to symptoms in the DSM-IV diagnosis of ADHD and are scored from 0 to 3 (0 = rarely or never, 3 = very often). The total 5 score is the sum of all of the item scores.
There Insomnia Page 22 of 86 Final Report Update 2 Drug Effectiveness Review Project was significant heterogeneity among the zopiclone studies (P=0 discount 4 mg ondansetron with visa symptoms type 2 diabetes. Subjective sleep duration in placebo-controlled trials of newer insomnia drugs Review: Insomnia Drugs Manuscript July 2008 (Copy of insomnia) Comparison: 01 Newer insomnia drugs vs placebo Outcome: 02 Subjective sleep duration Study Treatment Placebo WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI 01 Eszopiclone 3 mg vs placebo Zammit 2004 105 411 generic ondansetron 8mg on line medications you can take while nursing. Only eszopiclone 3 mg was significantly better than placebo on this outcome purchase genuine ondansetron medicine ubrania. Eszopiclone 3 mg shortened the time spent awake after sleep onset by 11 minutes compared with placebo (95% CI -20 to -2 minutes) generic ondansetron 8mg mastercard 98941 treatment code. Insomnia Page 23 of 86 Final Report Update 2 Drug Effectiveness Review Project Figure 4. Subjective wake time after sleep onset in placebo-controlled trials of newer insomnia drugs Review: Insomnia Drugs Manuscript July 2008 (Copy of insomnia) Comparison: 01 Newer insomnia drugs vs placebo Outcome: 03 Subjective WASO Study Treatment Placebo WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI 01 Eszopiclone 2 mg vs placebo Zammit 2004 104 53. Only eszopiclone was significantly better than placebo for this outcome. The difference was less than one awakening per night (mean difference -0. Insomnia Page 24 of 86 Final Report Update 2 Drug Effectiveness Review Project Figure 5. Subjective number of awakenings in placebo-controlled trials of newer insomnia drugs Review: Insomnia Drugs Manuscript July 2008 (Copy of insomnia) Comparison: 01 Newer insomnia drugs vs placebo Outcome: 05 Subjective number of awakenings Study Treatment Placebo WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI 01 Eszopiclone 2 mg vs placebo Zammit 2004 104 2. Data from varying doses of the same drug were combined for this indirect comparison. There were very few significant differences between the drugs on any outcomes. The exceptions were significantly shorter sleep latency and longer sleep duration with eszopiclone compared to ramelteon. On average, sleep latency was 11 minutes shorter with eszopiclone than ramelteon (95% CI -21 to -1. Sleep duration was an average of 37 minutes longer with eszopiclone than ramelteon (95% CI 17 to 56 minutes). Patients taking eszopiclone had significantly fewer awakenings than those taking zolpidem, but the difference was less than one time per night (mean difference 0. Insomnia Page 25 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 6. Adjusted indirect meta-analysis: Summary of results Mean difference (95% confidence interval) Sleep latency Sleep duration Number of WASO in minutes in minutes awakenings in minutes Eszopiclone a -11. We performed several subgroup analyses to determine if meta-analysis results varied by population or study design characteristics. When studies conducted in adult and elderly patients were analyzed separately, adjusted indirect analysis showed no significant differences between any of the drugs in subjective sleep latency or WASO (Table 7). In elderly patients, sleep duration was significantly longer with eszopiclone than with ramelteon and zolpidem in elderly patients, but there was no difference between any of the drugs in adult patients under age 65. Insomnia Page 26 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 7. Subgroup analysis by elderly and non-elderly adult patients Mean difference (95% confidence interval) Sleep latency Sleep duration Number of WASO in minutes in minutes awakenings in minutes Eszopiclone compared Adults -14. We also performed a subgroup analysis excluding studies that used doses other than the manufacturers’ recommended initial dose. Recommended initial doses are eszopiclone 2 mg, ramelteon 8 mg, zaleplon 10 mg, zolpidem 10 mg, and zopiclone 7. In fair-quality studies, eszopiclone significantly increased sleep duration compared with zolpidem (mean difference 37. PSG-measured outcomes in trials of ramelteon 77, PSG-measured sleep outcomes were reported in three placebo-controlled trials of ramelteon. The primary outcome, sleep latency at week 1 was reduced for both the 8 mg (32 minutes) and 16 mg (29 minutes) groups compared to placebo (48 minutes, P<0. Total sleep time was improved with ramelteon compared with placebo at weeks 1 and 3 but not week 5. There were no differences in WASO or number of awakenings. In a crossover study of 2 nights of treatment with ramelteon 4 mg, 8 mg, 16 mg, or 32 mg, all doses of ramelteon resulted in reductions in PSG-measured sleep latency (P<0. There were no differences in WASO for any of the treated groups compared to placebo. In a 2-night crossover study conducted in patients over age 65, there were significant improvements in PSG-measured sleep latency with ramelteon 4 mg (28. PSG-measured total sleep time was also improved with ramelteon (359 minutes for 4 mg and 362 minutes for 8 mg compared with 350 minutes for placebo; P=0. There was no difference in objective WASO with either dose of ramelteon compared to placebo, and there was an increase in number of awakenings with ramelteon 4 mg (but not with the 8 mg dose). Zolpidem extended-release There are no head-to-head trials comparing zolpidem extended-release with other newer drugs for insomnia. Evidence for the efficacy of zolpidem extended-release comes from three fair- 89, 115, 121 quality placebo-controlled trials. Additional information is provided in the FDA 79 statistical review of zolpidem extended-release Table 8 summarizes the results of these trials. Because they did not report means for subjective sleep outcomes at endpoint, we were not able to include their data in our meta-analysis. Insomnia Page 28 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 8. Placebo-controlled trials of zolpidem extended-release Author, year (Quality) Population Dose, duration Main efficacy results Primary outcome: Polysomnography-recorded WASO during first 8 hours of the night, mean difference from placebo (95% CI): Nights 1 and 2: -25 minutes (-34 to -16); P<0. This study included 2 nights of polysomnography recording, 12 nights of outpatient treatment, 2 more nights of polysomnography recording, 5 nights of outpatient treatment, and a 2-night placebo run-out to measure rebound. The primary outcome measure was polysomnography-recorded WASO in the first 8 hours of the night, measured on nights 1 and 2, and nights 15 and 16, with scores averaged over each 2-night period. WASO was significantly shorter with zolpidem-XR than placebo on nights 1 and 2, but not on nights 15 and 16. A post hoc analysis found that WASO was significantly better than placebo through hour 6, but not during hours 7 and 8 of the night, suggesting that the effects of zolpidem extended- 79 107 release did not persist past 6 hours. The publication of this trial reports only 6-hour results. Data for subjective sleep outcomes are reported graphically only. Results for subjective WASO, subjective number of awakenings, subjective sleep duration, and subjective sleep latency were mixed.
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A retrospective cohort study identifies subjects from past records and follows them from the time of those records to the present order ondansetron 8mg mastercard symptoms congestive heart failure. Combination Therapy: The use of two or more therapies and especially drugs to treat a disease or condition discount 4mg ondansetron with visa treatment 0f gout. Confidence interval: The range of values calculated from the data such that there is a level of confidence buy ondansetron 4mg with visa treatment 1 degree burn, or certainty generic ondansetron 4 mg medicines 604 billion memory miracle, that it contains the true value. The 95% confidence interval is generally used in Drug Effectiveness Review Project reports. If the report were hypothetically repeated on a collection of 100 random samples of studies, the resulting 95% confidence intervals would include the true population value 95% of the time. Confounder: A factor that is associated with both an intervention and an outcome of interest. Controlled clinical trial: A clinical trial that includes a control group but no or inadequate methods of randomization. Control group: In a research study, the group of people who do not receive the treatment being tested. The control group might receive a placebo, a different treatment for the disease, or no treatment at all. Convenience sample: A group of individuals being studied because they are conveniently accessible in some way. Convenience samples may or may not be representative of a population that would normally be receiving an intervention. Crossover trial: A type of clinical trial comparing two or more interventions in which the participants, upon completion of the course of one treatment, are switched to another. Direct analysis: The practice of using data from head-to-head trials to draw conclusions about the comparative effectiveness of drugs within a class or group. Results of direct analysis are the preferred source of data in Drug Effectiveness Review Project reports. Dosage form: The physical form of a dose of medication, such as a capsule, injection, or liquid. The route of administration is dependent on the dosage form of a given drug. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. Dose-response relationship: The relationship between the quantity of treatment given and its effect on outcome. In meta-analysis, dose-response relationships can be investigated using meta- regression. Double-blind: The process of preventing those involved in a trial from knowing to which comparison group a particular participant belongs. While double-blind is a frequently used term Second-generation antidepressants 183 of 190 Final Update 5 Report Drug Effectiveness Review Project in trials, its meaning can vary to include blinding of patients, caregivers, investigators, or other study staff. Double-dummy: The use of two placebos in a trial that match the active interventions when they vary in appearance or method of administrations (for example, when an oral agent is compared with an injectable agent). Effectiveness: The extent to which a specific intervention used under ordinary circumstances does what it is intended to do. Effectiveness outcomes: Outcomes that are generally important to patients and caregivers, such as quality of life, responder rates, number and length of hospitalizations, and ability to work. Data on effectiveness outcomes usually comes from longer-term studies of a “real-world” population. Effect size/estimate of effect: The amount of change in a condition or symptom because of a treatment (compared to not receiving the treatment). It is commonly expressed as a risk ratio (relative risk), odds ratio, or difference in risk. Efficacy: The extent to which an intervention produces a beneficial result under ideal conditions in a selected and controlled population. Equivalence level: The amount which an outcome from two treatments can differ but still be considered equivalent, as in an equivalence trial, or the amount which an outcome from treatment A can be worse than that of treatment B but still be considered noninferior, as in a noninferiority trial. Equivalence trial: A trial designed to determine whether the response to two or more treatments differs by an amount that is clinically unimportant. This lack of clinical importance is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence level of clinically acceptable differences. Exclusion criteria: The criteria, or standards, set out before a study or review. Exclusion criteria are used to determine whether a person should participate in a research study or whether an individual study should be excluded in a systematic review. Exclusion criteria may include age, previous treatments, and other medical conditions. External validity: The extent to which results provide a correct basis for generalizations to other circumstances. For instance, a meta-analysis of trials of elderly patients may not be generalizable to children. Studies are assumed to be measuring the same overall effect. Fixed-dose combination product: A formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses. Forest plot: A graphical representation of the individual results of each study included in a meta- analysis and the combined result of the meta-analysis. The plot allows viewers to see the heterogeneity among the results of the studies. The results of individual studies are shown as squares centered on each study’s point estimate. A horizontal line runs through each square to show each study’s confidence interval—usually, but not always, a 95% confidence interval. The overall estimate from the meta-analysis and its confidence interval are represented as a diamond. The center of the diamond is at the pooled point estimate, and its horizontal tips show the confidence interval. Second-generation antidepressants 184 of 190 Final Update 5 Report Drug Effectiveness Review Project Funnel plot: A graphical display of some measure of study precision plotted against effect size that can be used to investigate whether there is a link between study size and treatment effect. Half- life: The time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. Harms: See Adverse Event Hazard ratio: The increased risk with which one group is likely to experience an outcome of interest. For example, if the hazard ratio for death for a treatment is 0. Head-to-head trial: A trial that directly compares one drug in a particular class or group with another in the same class or group. Health outcome: The result of a particular health care practice or intervention, including the ability to function and feelings of well-being. For individuals with chronic conditions – where cure is not always possible – results include health-related quality of life as well as mortality. Heterogeneity: The variation in, or diversity of, participants, interventions, and measurement of outcomes across a set of studies.