The Role of Noncomparative Evidence in Health Technology Assessment Decisions.

BACKGROUND: Many health technology assessment (HTA) agencies express a preference for randomized controlled trial evidence when appraising health technologies; nevertheless, it is not always feasible or ethical to conduct such comparative trials. OBJECTIVES: To assess the role of noncomparative evidence in HTA decision making. METHODS: The Web sites of the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, and the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [IQWiG]) in Germany were searched for single HTA reports (published between January 2010 and December 2015). The product, indication, outcome, and clinical evidence presented (comparative/noncomparative) were double-extracted, with any discrepancies reconciled. A noncomparative study was defined as any study not presenting results against another treatment (including placebo or best supportive care), regardless of phase or setting, including dose-ranging studies. RESULTS: A total of 549 appraisals were extracted. Noncomparative evidence was considered in 38% (45 of 118) of NICE submissions, 13% (34 of 262) of CADTH submissions, and 12% (20 of 169) of IQWiG submissions. Evidence submissions based exclusively on noncomparative evidence were presented in only 4% (5 of 118) of NICE appraisals, 6% (16 of 262) of CADTH appraisals, and 4% (6 of 169) of IQWiG appraisals. Most drugs appraised solely on the basis of noncomparative evidence were indicated for cancer or hepatitis C. Positive outcome rates (encompassing recommended/restricted/added-benefit decisions) for submissions presenting only noncomparative evidence were similar to overall recommendation rates for CADTH (69% vs. 68%, respectively), but were numerically lower for NICE (60% vs. 84%, respectively) and IQWiG (17% vs. 38%, respectively) (P > 0.05 for all). CONCLUSIONS: Noncomparative studies can be viewed as acceptable clinical evidence by HTA agencies when these study designs are justifiable and when treatment effect can be convincingly demonstrated, but their use is currently limited.

Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers.

AIMS: To investigate the effects of the D2-receptor agonist pramipexole with and without the co-administration of the peripherally acting D2-receptor antagonist domperidone on measures of alertness, autonomic and endocrine function. METHODS: Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons. RESULTS: The pre-post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F(3,45) = 8.39, P < 0.001), initial diameter of the light reflex response (F(3,42) = 3.78, P < 0.05), and light (F(3,45) = 5.21, P < 0.005) and dark (F(3,45) = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations. CONCLUSIONS: The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2-receptors.

Modulation of the acoustic startle response by the level of arousal: comparison of clonidine and modafinil in healthy volunteers.

A sudden loud sound evokes an electromyographic (EMG) response from the orbicularis oculi muscle in humans together with an auditory evoked potential (AEP) and an increase in skin conductance (SC). Startle responses are inhibited by weak prepulses (prepulse inhibition, (PPI)) and may also be modified by the level of alertness. We compared the sedative drug clonidine and the alerting drug modafinil on sound-evoked EMG, AEP, and SC responses, on the PPI of these responses and on level of arousal and autonomic functions. Sixteen healthy male volunteers participated in four weekly sessions (clonidine 0.2 mg, modafinil 400 mg, their combination, placebo) in a double-blind, cross-over, balanced design. Responses were evoked by sound pulses of 115 and 85 dB (PPI) for 40 ms and recorded conventionally. Level of alertness, autonomic functions (pupil diameter, blood pressure, heart rate, salivation, temperature) and the plasma levels of the hormones prolactin, thyroid-stimulating hormone and growth hormone were also measured. Data were analyzed with analysis of variance with multiple comparisons. Both prepulses and clonidine attenuated all three startle responses and modafinil antagonized clonidine's effects on the EMG and AEP responses. None of the drugs affected PPI. Clonidine showed sedative and sympatholytic effects, and modafinil showed alerting and sympathomimetic effects. In conclusion, startle responses were susceptible not only to PPI but also to the level of arousal.