Is bigger better? An argument for very low starting doses

Lower-dose prescriptions in the post-marketing situation and the influencing factors thereon

“…On the contrary, previous reports have suggested that the efficacy at low doses is not sufficiently studied during the development period because phase III trials mainly focus on the confirmation of efficacy; this is one of the reasons for the use of a lower dose of a drug postmarketing [1,6]. In the present study, although there was no statistically significant difference, several products of "lower dose in pivotal study" corresponded to "lower-dose prescription drugs."…”

“…Defined daily dose (DDD), an average daily dose for adults in the primary indication defined by the World Health Organization (WHO), was changed in the post-marketing phase for 115 products between 1989 and 2000, and approximately 60% of them indicated a change to a lower dose [2]. It has been reported that although a lower-dose prescription is often recommended for the elderly population and for reducing side effects [3][4][5][6], clinical evidence on using such a low dose is not reflected in the product label (package insert), even if it is published in medical journals [7][8].…”

“…To the best of our knowledge, the actual situation of post-marketing prescription of specific products has not been fully investigated so far. Some studies have reported that, in the clinical development process, phase III trials are often performed using doses close to the maximum tolerated dose (MTD) to focus on the efficacy, and the lower doses of a drug are not sufficiently examined [1,6,9]. However, there is no evidence supporting the fact that this is the cause of lower-dose prescriptions in the post-marketing phase.…”

Deliberate clinical inertia: Using meta‐cognition to improve decision‐making

“…What may help in such situations is for clinicians to gain confidence in thinking more probabilistically (by balancing the likelihood of the diagnosis they fear most versus estimating and noting the likelihood of the diagnosis most favoured given all the clinical features in the medical record -'probabilistic notation') 15 and acting expectantly by treating the condition most favoured and reassess as circumstances evolve ('slow diagnosis'). 15 In the case study, uncomplicated mild cellulitis in a young immunocompetent patient is the most likely diagnosis based on clinical presentation and can be treated expectantly with oral antibiotics ('stepped care') 9,16 and advice to the patient to return if the condition worsens, with explicit time-specific and action-specific instructions ('safety netting'). 9,17,18 The other features of the case are the diagnostic momentum, 12 framing effect 12 and groupthink, which fed into the ensuing cascade of overtreatment administered by a sequence of different clinicians.…”

“…Can be used for both diagnostic and treatment uncertainties.Tincture of timeSince many conditions are self-remitting, or the indications for intervention become clearer with time, the 'tincture of time'24 can be used as an alternative to zebra hunting, test cascades and immediate instigation of treatments. Requires good skills in safety netting.Slow diagnosisDo not rush to a diagnosis and instead focus on the problem and avoid premature use of labels that may not be needed immediately, or sometimes, ever 15,23.…”