Placebos 1.Ethical Issues 2.Problems with active control non- inferiority studies 3.Design modifications that may make placebo controls more acceptable

Use of Placebos Three Cases 1.No available therapy Generally no objection to placebo control. No real alternative in symptomatic conditions 2.Well-established effective therapy for group Use of placebo (or placebo plus active - 3 arm study) acceptable in symptomatic treatments, but not when denial or deferral of therapy leads to harm - death or irreversible morbidity Pediatric concern: Lack of valid patient consent (but possible assent). Does adult conclusion apply? Possible need for placebo to have informative study still relevant

Use of Placebos (cont.) 3.Well-established therapy in adults, but not children, that is life-saving or morbidity preventing. When is it legitimate to test important outcomes in the new group in the face of known adult benefit (i.e, may be very strong prior) There may be study design changes that can make pediatric studies more comfortable but still gain adequate data

Alternative Study Designs 1.Add-on Rx When receipt of no therapy in a placebo group is not acceptable, an add-on study may be Randomize to standard plus test drug vs. standard plus placebo (patients usually are already on standard of time of randomization) Can also introduce D/R and, sometimes can withdraw standard Gives clear evidence of effect, but no data on monotherapy Usual in antiepileptic pediatric studies

Add on Trial std plus test dose 1 dose 2 standard dose 3 std plus placebo

Alternative Study Designs (cont.) 2.Studies in non-responders to available therapy This avoids denial of a useful available therapy but gives data on a different group that may be less responsive or non- responsive To know whether the new drug was really superior (as opposed to “merely” effective) in that population, you need to randomize to the failed drug and test drug and show superiority. A placebo-controlled trial will show effectiveness but will not usually demonstrate effectiveness in non- responders (in the sense of knowing the patients would not have responded equally well to the “failed” drug)

Studies in Non-Responders standard drug non-responder new drug

Alternative Study Designs (cont.) 3.Designs that limit duration of exposure to ineffective treatment a.Early escape/early advance Even if a placebo can be used in trials of symptomatic therapies, prolonged treatment with ineffective agent may be uncomfortable, especially in children Many trial designs can introduce an early escape (or early advance if a crossover) provision in which patients failing to improve to a defined extent (or who worsen) at some specified time or at any time are considered completers or failures. Their last value can be carried forward for a conventional analysis or ability to complete can be used as an efficacy endpoint

Alternative Study Designs (cont.) b.Randomized Withdrawal Early escape can leave too few patients treated for the duration of interest, but in general very long placebo-controlled trials may be uncomfortable or undoable in children. A remedy is the randomized withdrawal trial (Amery 1975), initially proposed for angina trials This design, aside from showing effectiveness 1.Gives information on long term effects without long-term placebo 2.Needs care re withdrawal effects (narcotics, nitrates) 3.Is enriched with responders (can overestimate effect in naïve patients) 4.Can follow patients for a defined period and have early escape features 5.If there is an existing open protocol, eases recruitment

Randomized Withdrawal test drug dose 1 dose 2 test drug responders dose 3 placebo

Alternative Study Designs (cont.) 4.Asking a different (shorter or PD) question Given adult data, it may not be necessary to carry out the same trials in children. (Note, we can conclude drugs would be expected to behave similarly in children and do no studies.) For example a.In HT, typical adult placebo-controlled study 4-12 weeks. Would a one-week trial in children suffice, perhaps with a randomized withdrawal trial after a longer period? b.In seasonal allergy trials, large size often needed because of variable pollen and possibly other reasons. “Chamber” studies (introduced “antigen) usually smaller and more sensitive; would they be sufficient?

Different Question (cont.) c.Could short-term pediatric data (one dose analgesic studies) support the efficacy of a drug intended for long-term pediatric analgesic use