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Table 1 Case studies illustrating scenarios requiring causal estimation

From: A framework for the design, conduct and interpretation of randomised controlled trials in the presence of treatment changes

Causal estimation scenario Case study Treatment changes adjusted for Causal question being addressed
Interest in efficacy despite pragmatic trial design
  MRC hypertension trial Addition of alternative treatments due to inadequate blood pressure control, or switches to alternative treatments due to side effects Treatment efficacy in absence of treatment switches or additions
  SANAD trial Withdrawal from randomised treatment, addition of alternative treatments, or switches to alternative treatments due to inadequate seizure control Treatment efficacy in absence of treatment changes due to inadequate seizure control
Trial protocol differs from practice
  Vitamin A trial Non-receipt of trial drug due to failure of the drug distribution system Treatment efficacy among those who would have complied with active treatment if randomised to receive it
Contamination (control arm receives intervention)
  Honey trial More extreme forms of treatment, such as antibiotics, surgery or radiotherapy
Patient or clinician decision to switch from conventional dressings to honey
Treatment efficacy in absence of any treatment changes
  PACIFICO trial Switches from standard to new treatment on disease progression Treatment efficacy in absence of treatment switches from standard to new treatment on progression
Interest in efficacy if taken as prescribed
  Coronary Drug Project Failure to take treatment according to prescribed schedule Treatment efficacy among those who complied with treatment protocol
  1. MRC Medical Research Council, PACIFICO Purine-Alkylator Combination In Follicular lymphoma Immuno-Chemotherapy for Older patients, SANAD Standard and New Antiepileptic Drugs