Clinical Trials Approach and the Pediatric Trials Network Danny Benjamin, MD, PhD, MPH Professor, Duke University

Support and Conflict of Interest Pediatric Trials Network – Best Pharmaceuticals for Children Act – National Institute of Health – NICHD – – Duke Clinical Research Institute ( – Collaboration: Duke, Children’s Mercy Hospital, UCSD, CNMC, CHOP, and 100 clinical sites Conflicts of Interest –

Pediatric Trials Network Sponsored by NICHD and the BPCA 30 molecules under study; studies conducted under an IND Primarily PK/PD and safety trials 4/10 methods “steps” in pediatric trials Initial results from Pediatric Trial Network- supported studies

Methods Concept #1: Inclusion/Exclusion Criteria “Typical” study 1) Ages years 2) Hospitalized and receiving empiric parenteral antibiotic therapy 3) Body mass index of ) Able to communicate effectively with the study personnel 5) Written informed consent from parent or other legally acceptable guardian, and informed assent from subject 6) Willingness and ability to comply with all study procedures Antimicrobial 1) < 28 weeks gestation at birth 2) > 48 hours and < 121 days of age at the time of study drug administration 3) 1 of the following – Suspected systemic infection – Receiving product for prophylaxis – Receiving product for treatment of a systemic infection 4) Written consent from parent or other legally acceptable guardian

Methods Concept #1: Inclusion/Exclusion Criteria 1) Hypersensitivity or allergic reaction 2) Pregnant or nursing, if female 3) Hormonal contraceptives 4) Probenecid administration 5) Epilepsy or seizure disorder 6) Weight < 34.0 kg (75.0 lb) 7) Creatinine clearance (CrCl) ≤ 80 mL/minute) 8) AST or ALT level > 3x ULN; total bilirubin > 2- fold ULN 9) Life expectancy < 3 months, clinically unstable, critically ill, signs or symptoms of sepsis or shock, or condition is expected to deteriorate on Study Day 1 or 2 10) History of a significant disease or condition (medical or surgical) that, in the opinion of the investigator, would place a subject at risk, compromise the quality of the data, or interfere with the absorption, distribution, metabolism, or excretion of the product Antimicrobial 1) History of anaphylaxis 2) Exposure to product in the month prior to study 3) Serum creatinine > 1.7 mg/dL

Meropenem PK in Young Infants Please note, these data are from an interim analysis

Methods Concept #1: Inclusion/Exclusion— Summary Broad inclusion criteria Limited exclusion criteria Variability: – If present, needs to be shown – Sepsis and critically ill – One dose may not fit all Ethical—potential benefit Societal “good” – Feasible studies are achievable (within trial) – Limited number of units and investigators (between trials) – Lower cost means it is more likely that more studies will be completed

Method Concept #2: Sampling Times and Assay Industry sampling strategy for daily administered drug Pre-dose Peak 1 hour 2 hours 4 hours 8 hours 12 hours 16 hours 24 hours (trough) Oh, yeah, 1 cc each

Methods Concept #2: Sampling Times Adult design – Blood volume – 500 gm infant – Adult example 9 samples – Pre-dose – Peak – 1 hour – 2 hours – 4 hours – 8 hours – 12 hours – 16 hours – 24 hours (trough) Infant design – Get assay down – Take advantage of daily labs – 3-4 samples total Group 1 – Peak – 4 hours – 12 hours – Trough Group 2 – 1 hour – 8 hours – 16 hours – Trough Time windows to help with glucose checks

Sampling Times: Meropenem Dose 1 PK-odd Group (infants with birthday on an odd date; e.g., 1 st, 3 rd, 5 th, etc.) 1) Pre: any time in the 24 hours prior to the first dose 2) Peak: 30 minutes to 1 hour after completion of first dose 3) 3-4 hours after completion of first dose 4) Trough: within 2 hours prior to second dose Dose 1 PK-even Group (infants with birthday on an even date; e.g., 2 nd, 4 th, 6 th, etc.) 1) Pre: any time in the 24 hours prior to the first dose 2) Peak: 1-2 hours after completion of first dose 3) 4-6 hours after completion of first dose 4) Trough Dose 5 PK-steady state (around 5 th dose: may be done around the 4 th, 6 th, 7 th dose) 1) Pre: any time in the 3 hours prior to the 5 th dose 2) Peak: 15 minutes-2.5 hours after completion of 5 th dose 3) 4-12 hours after completion of 5 th dose

Methods Concept #2 Sample Timing: Fluconazole

Methods Concept #2: Assay and Sample Timing – Summary Have gone from 9 cc of blood to 300 ul-700 ul Have gone from 7 sticks minimum to 1-2 sticks maximum Even these 2 sticks may be avoided because of the generous time windows (combined with a blood gas or a glucose)

Methods Concept #3: Scavenge Sampling A sampling strategy whereby blood is “scavenged” from samples that otherwise go into the trash Every day, premature infants have routine labs (variable by site) for chemistry (parenteral nutrition), etc. E.g., the nurse may obtain samples of 100 ul, but only 50 ul is needed for the lab; thus, 50 ul will normally be discarded If assay is ~50 ul or less, then the sample can be split at the machine, blood can be picked up by the study coordinator, processed, and saved

What We Are Learning About Scavenge Initially – Most academicians hated the idea – Many clinical pharmacologists were skeptical but open-minded – Bedside clinicians loved it Product stability, product half-life, and assay technical components are key – Accuracy of sample collection time – How long it sits in the lab – Only so much blood and multiple types of tubes Motivated investigators (some none, some per patient) Need traditional sampling linked to scavenge within trial and for most enrollees, within each patient Longer “window” to collect works well with motivated investigators – Fluconazole for 6 weeks – Meropenem multiple doses – Single-dose study

Methods Concept #3: Where We Have Used Scavenge Polyclonal and monoclonal antibodies to prevent staphylococcal infections (3 trials including Benjamin et al., J Perinatology, 2006) Fluconazole (4 trials including Wade, Benjamin et al., PIDJ, 2010) Ampicillin (Benjamin et al., SPR) Piperacillin tazobactam (Cohen-Wolkowiez, Benjamin et al., 2011) Meropenem Metronidazole (Cohen-Wolkowiez, Benjamin et al., 2011)

Methods Concept #4: Opportunistic Study Insanity is doing the same thing, expecting different results Short version of drug development in the nursery—use products repeatedly, complain that drug companies don’t study the products, and continue to use products for decades until the next product comes along. Repeat. Patient has a rare problem and needs a drug almost never used in the NICU. Guess at the dose. Repeat. Try something new.

Methods Concept #4: Opportunistic Design Inclusion Criteria: Infants who are receiving understudied drugs of interest per standard of care as prescribed by their treating caregiver Exclusion Criteria: Failure to obtain consent Dosing information, safety data, samples, and (potentially) PD marker if enough infants are enrolled PK sampling times: pre- specified by dosing interval Obtain key time points Have the option to modify time points via conference call with the investigators once enough infants have been enrolled

Methods Concept #4: Opportunistic Goals For the extremely rare event (mycoplasma meningitis), provide a very limited amount of exposure data—this may be in the form of a case report or “case series” For commonly used drugs (metronidazole), provide preliminary data to help design a traditional PK study (or PK-safety study) Data can later be combined with more data from more traditional designs

Metronidazole Clearance

Methods Concept #4: Opportunistic Metronidazole – Summary Advantages of conducting the opportunistic – Going into the traditional PK study, we knew to design based on post-menstrual age – Sampling times were both parsimonious and robust – Mid-trial correction possible – Submitted the data into peer review from the opportunistic study – Total patients studies from 24 to 50