Transcript Optimizing Pediatric Clinical Trial Design

Clinical Trials Approach
and the Pediatric Trials Network
Danny Benjamin, MD, PhD, MPH
Professor, Duke University
Support and Conflict of Interest
• Pediatric Trials Network
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Best Pharmaceuticals for Children Act
National Institute of Health
NICHD
https://pediatrictrials.org
Duke Clinical Research Institute (https://www.dcri.org)
Collaboration: Duke, Children’s Mercy Hospital, UCSD,
CNMC, CHOP, and 100 clinical sites
• Conflicts of Interest
– https://www.dcri.org/about-us/conflict-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 Networksupported studies
Methods Concept #1:
Inclusion/Exclusion Criteria
“Typical” study
Antimicrobial
1) Ages 12-17 years
2) Hospitalized and receiving empiric
parenteral antibiotic therapy
3) Body mass index of 18-30
4) 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
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 > 2fold 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
Median Meropenem Steady-State 75% DI Conc
Meropenem Conc at 75% of Dose Interval (mcg/ mL)
36
32
28
24
20
16
12
8
4
0
GA <32WK
PNA <2WK
GA <32WK
PNA >=2WK
GA >=32WK
PNA <2WK
Age Group Strata
GA >=32WK
PNA >=2WK
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
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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
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Peak
4 hours
12 hours
Trough
• Group 2
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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., 1st, 3rd, 5th, 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., 2nd, 4th, 6th, 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 5th dose: may be done around the 4th, 6th, 7th dose)
1) Pre: any time in the 3 hours prior to the 5th dose
2) Peak: 15 minutes-2.5 hours after completion of 5th dose
3) 4-12 hours after completion of 5th 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 20-30 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: prespecified 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