Editorial commentary: effectiveness or efficacy: which study to evaluate antibiotics in neonates?

Although the drug licensing process was introduced to ensure that medicines are safe, up to 90% of products are used in an unauthorized or off-label manner in the neonatal population, especially if neonates are treated in neonatal intensive care units (NICUs). This is also the case for the use of meropenem, a broad-spectrum antibiotic that is active against many multidrug-resistant bacteria. Meropenem is approved in the United States since 1996 and in Europe since 1997 for the treatment of bacterial meningitis and/or complicated intra-abdominal infections in children ≥3 months of age. However, meropenem is frequently used in an off-label manner in infants <3 months of age and especially for the treatment of neonatal infections. For this reason, the evaluation of meropenem in neonates started a few years ago. Two population pharmacokinetic (PK) studies demonstrated that clearance was dependent on gestational and postnatal ages [1, 2]. In this issue of Clinical Infectious Diseases, Cohen-Wolkowiez and coauthors report the results of an openlabel study evaluating the safety and effectiveness of meropenem in neonates [3]. This important study involved 19 pediatric or neonatal US departments and included 200 neonates of various gestational and postnatal ages. Based on the PK data, the dosage regimen was adapted to bodyweight and gestational and postnatal ages. Effectiveness (ie, the extent to which a treatment achieves its intended purpose) was defined as a patient being alive, with negative bacterial cultures from sterile body fluid and with a presumptive clinical cure score ≥7, after meropenem treatment. The study began in June 2008 (clinical trials registration NCT00621192), and the results of the study have been accepted for publication. Additional data on efficacy will be provided by 2 studies called NeoMero 1 and NeoMero 2 (NTC01551394 and NT015544124, respectively), both conducted in Europe in infants <90 days of age with bacterial meningitis or lateonset sepsis. At completion date (estimated to be July 2014), meropenem will have a complete and very informative evaluation in neonates, conducted step by step, based on a population PK study, the intermediate effectiveness and safety evaluation published today, a randomized controlled trial for efficacy in neonatal sepsis, and additional PK data in neonatal meningitis. This will hopefully allow a marketing authorization for meropenem in neonates for the treatment of suspected or proven infection, including complicated forms (intra-abdominal infection, meningitis), but obtained >15 years after marketing authorization in infants. Although such a plan is ideal, obviously it is a long process that cannot be undertaken for all drugs requiring evaluation in neonates because of a low population size with a large variation of diseases, ethical limitations, regulatory requirements, length of studies, costs, and lack of trained investigators. Therefore, the question remains of how to evaluate antibiotics in neonates: Is a randomized controlled trial (RCT) always required for an effective and safe use of antibiotics in neonates or to receive a marketing authorization? Although RCT is the gold standard to demonstrate efficacy, the obligation of conducting RCT trials when antibacterial efficacy has already been established in other pediatric age groups and in adults may be questioned as they may be extremely difficult, if not impossible, to conduct for many reasons, including the following: