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treatments are in widespread use. We know a lot about the risks and benefits.
We just do not know the relative risks and benefits. Thus, as part of the
consent process, we must explain what is known, what is not known, and
what we hope to learn by doing the study.
Second, in studies of new therapies, the treatment that patients will get if
they do not enroll in the study is clear. They will get the same treatment as
patients in the control arm, that is, the existing standard of care. In CER, by
contrast, there is no obvious “default” position. Prospective study subjects
must be told that if they do not enroll in the study, they might get the exact
same treatment that they would have gotten if they had enrolled in the trial.
They should also be told whether and how treatment will be different if they
enroll in the study.
Finally, in any clinical situation, prospective study subjects must be told
about the potential harms that they (or their child) face from their underlying
disease, regardless of whether or not they enroll in the trial. For premature
babies, all parents should be told of the long-term complications of
prematurity. They need to understand that premature babies can die or can
survive with eye disease, blindness, chronic lung disease, and
neurodevelopmental impairment. This is not an easy conversation to have.
There has been much discussion and debate among expert clinicians about
how to explain these potential harms.
40,41
The process of informed consent for any prospective randomized trial is
difficult. We know from studies of consent in other situations that parents
often have trouble understanding randomization. For example, Kodish and
colleagues have shown that half of parents who consented for their children
to be in a study of cancer chemotherapy did not understand randomization.
42,43
Part of the problem may be that consent forms themselves, while
designed to inform and empower parents, are often long and confusing. They
could be simplified. Lantos and Feudtner suggest that it would have been
sufficient, and perhaps more informative, to replace the traditional consent
form with one that simply said the following:
Your baby was born extremely prematurely. Many babies who are born
this early die. Many of those who survive have long-term complications,
including eye disease, chronic lung disease, cerebral palsy, and brain
damage. Most survivors, however, do not have any of these problems. We
are doing a study to try to learn the best ways to prevent these things from
happening. The study involves giving babies two different levels of oxygen:
higher and lower. Some babies in the study may do better—and some
babies worse—than other babies in the study. But we don’t know which
group will have better outcomes. (If we knew, we wouldn’t be doing the
study.) Right now, babies in NICUs across the United States receive both
levels of oxygen and many levels in between. We also don’t know whether
babies in the study will have better or worse outcomes than babies who are
not in the study. For babies in the study, we will decide what oxygen level
to provide by a random choice (similar to flipping a coin.) Every baby will
have a 50-50 chance of getting either low or high oxygen levels. Babies
who are not in the study are treated according to our NICU protocol. You
can decide whether to be in the study or not. If you decide to be in the
study, this decision will only determine the level of oxygen that we use and
will not affect the care that your baby gets in any other way.
44
CONCLUSION
Our regulations governing research in children offer general guidelines that
are designed to protect children from harm or exploitation. These important
protections can sometimes lead to disagreements about whether particular
studies are ethically permissible. Controversies arise in studies that involve
genomics, healthy children, and sick babies. They focus on psychological
harms and benefits as well as physical ones. In some cases, they turn on
subtle issues of epistemology—that is, when do we know enough and when
are we uncertain enough that randomization is justifiable.
In each controversial area, the challenge for researchers and policy
makers is to use the framework of minimal risk or acceptable risk–benefit
ratio in order to determine whether the study is permissible. We then need to
pay meticulous attention to informing parents and older children. The
application of the basic principles of research ethics to the practicalities of
the specific research projects requires careful attention to the details of the
study, flexibility in the application of the principles, and open deliberation
about the complex judgments that must be made.
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Tomoyuki Mizuno
Philip D. Walson
Alexander A. Vinks
C H A P T E R
7
Precision Medicine and Therapeutic Drug Monitoring
INTRODUCTION
Most medical treatments currently on the market come with recommendations
for the average patient. However, there is often substantial between- and
within-patient variability in drug exposure and response to many medications
when administered at the labeled dose. In addition, children (especially
infants) undergo rapid dynamic changes in their body size and physiology,
which have an impact on the variability in drug exposure and response.
Therefore, when using a “one-size-fits-all” approach, treatments can be
successful for some patients, but not for others. Precision medicine is an
innovative approach to this problem which tailors drug treatments to
individual needs based on patient-specific factors, including genotype,
demographic, and clinical characteristics; environment; and lifestyle. The
simplest way to identify and adjust for interindividual variability in drug
response is to objectively measure the degree of effect and then adjust the
dosing regimen accordingly. However, such a straightforward approach is
seldom feasible, as simple and reliable therapeutic effect measures are not
always available in routine clinical situations. In addition, many serious
conditions require rapid attainment of adequate clinical effect while avoiding
excessive dosing in clinical conditions where drug effects are especially
difficult to measure. This is particularly true in newborns and other nonverbal
or noncommunicative patients. Rational pharmacotherapy requires a basic
understanding of the way patients handle drugs (pharmacokinetics, PK) and
their response (effect) to specific drug concentrations (pharmacodynamics,
PD).1 PK may be simply defined as what the body does to the drug, as
opposed to PD, which may be defined as what the drug does to the body.
2
During the past decades, significant advances have been made in the field of
pediatric and neonatal PK and PD, including a better understanding of the
effects of growth (size) and development (or maturation) on organ function
and drug dose–exposure–effect relationships.3 The ultimate goal of the study
of dose–exposure–effect relationships is to allow clinicians to derive
optimal, individualized dosing regimens, which produce maximal therapeutic
and minimal side effects with the simplest dosing regimen possible. This can
best be achieved by linking PK and PD information to better understand or
predict the exposure–effect relationship in a time-dependent (dynamic)
manner. The proper measurement and interpretation of drug concentrations
[therapeutic drug monitoring (TDM) or the more proactive term
“management”4] in a specific patient can help us better understand how a
particular drug is behaving and is required for further individualization of the
dosing regimen in that patient as well as how to best select an initial dosing
regimen in future patients.
5
PRECISION MEDICINE
Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their
treatments as best they can to individuals. You can match a blood transfusion to a blood type—that was
an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as
standard? What if figuring out the right dose of medicine was as simple as taking our temperature?
—President Barack Obama, State of the Union Address, January 20, 2015
The statement in the 2015 State of the Union that most medical treatments are
designed for the average patient initiated the rollout of the Precision Medicine
Initiative, a broad research effort to revolutionize how health care and
treatment of disease can be more precise, personalized, and improved.
6
Precision medicine is an innovative approach that considers individual
differences in patient’s genes, environments, and lifestyles for better clinical
decision-making in treatment of disease and in health care. Progress in
precision medicine has already led to powerful new discoveries and several
new treatments that are tailored to specific characteristics, such as a patient’s
genotype or the genetic profile of an individual’s tumor.
Therapeutic optimization can be viewed as the continuum of improving
practice-changing paradigms across the spectrum of disease-specific
pharmacologic interventions and, as such, forms an important keystone of
precision medicine.7 In the pediatric and neonatal populations, therapeutic
optimization is more challenging than in the adult population as evidence for
dosing, efficacy, and safety of many medications is sparser. Therefore, the
dosage regimen is frequently determined by extrapolation from adult clinical
data and by a “trial-and-error” paradigm. This can be successful for some
patients and some medications but may lead to unsafe or ineffective dosing for
others, especially in very young children. The biggest challenge for
implementation of precision medicine in the pediatric populations is to
identify age-appropriate and evidence-based safe and effective dose ranges
across the age spectrum from newborns to adolescents. A better understanding
of the age-related dynamic changes in PK/PD characteristics is important to
establish dosing strategy and implement therapeutic optimization in the
pediatric populations.
THE TARGET CONCENTRATION STRATEGY
Drug actions (effects) are directly related to the drug concentration at the
site(s) of action. Although imperfect, there is almost always a better
relationship between the effect of a given drug and its concentration in the
blood than between the dose of the drug given and the effect. PK is the science
that can explain and predict the relationship between a dosing regimen and the
concentration of a drug in various body compartments over time. A basic
understanding of PK principles and how these principles are altered in the
developing child is required to better understand and predict drug actions.
The interrelationship between drug input (dose), PK, PD, and clinical effects
is schematically conceptualized in Figure 7.1.
8
Figure 7.1 Schematic representation of the interrelationships between drug input (dose),
pharmacokinetics (concentration), pharmacodynamics, and clinical effects. (Adapted from Danhof M.
Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models. J
Pharmacok inet Pharmacodyn 2015;42:447–462.)
There are many practical, physiologic, and pathophysiologic factors that
determine how much drug effect will be associated with a drug prescription.
Clinicians make a diagnosis and then prescribe a dosing regimen: drug, dose,
formulation, route, frequency, and duration. Once a drug is prescribed, there
are many factors that determine how much effect, either therapeutic or toxic, is
seen in the individual patient. Prescriptions must be filled correctly, the
prescription filled must contain the correct drug and amount, the dosage
regimen must be taken/given (adherence), and the drug must get into the
patient and reach the site(s) of action. There are many reasons why
concentrations and drug exposure (and therefore the effects) that result from
prescriptions differ among patients. Even if taken or given exactly as desired,
effects produced will depend on many factors, including the patient’s
physiology, prior history, and other drugs present. Patients/parents may never
fill the prescription. Up to 25% of patients do not fill prescriptions, and even
more do not take medication as indicated. Children and adolescents with
chronic illness have great difficulty completing prescribed treatment
regimens, which can be complex and burdensome. High rates of nonadherence
to treatment (up to 50% or more) have been reported for various pediatric
chronic conditions, such as asthma, epilepsy, transplantation, juvenile
rheumatoid arthritis (JRA), and diabetes.
9–11
Different formulations of the
same drug may have different absorption characteristics. Manufacturing
problems can and do occur. Pharmacy or pharmaceutical errors can alter the
amount of drug delivered or in fact which drug is given, and parents or
patients may or may not comply with instructions. All of these factors can
alter the amount of drug that reaches the site of action. Several studies have
documented unpredictable drug delivery in neonates. This is especially
relevant for antibiotics such as aminoglycosides that are used frequently to
treat bacterial infections in this population. A lack of appreciation of drug
delivery issues such as the small volumes and low infusion rates used in these
patients can result in a much lower-than-expected blood concentrations and
much lower than what is required for optimal antimicrobial therapy.12 Drug
concentration measurements can provide an objective way to identify, explain,
or eliminate uncertainty caused by a number of these factors, especially in
patients who have unusual or unexpected drug responses. However, even
patients who actually take or are given the same amount of a drug may also
have very different amounts of drug in their body or blood at different times
after dosing. The ability to predict and explain the inter- and intraindividual
differences in drug concentrations over time requires knowledge of basic PK
principles.
THE CONCEPT OF THERAPEUTIC DRUG
MONITORING
TDM is a multidisciplinary clinical specialty aimed at improving treatment of
disease and patient health care by individually tailoring a dosage regimen of
drugs based on the measurement made in the laboratory with appropriate
interpretation.13 The measurement can be a genotype, demographic and
clinical data, drug concentration in a biologic matrix (e.g., blood), and/or
biomarkers to represent drug response. A priori TDM is defined by the
International Association of Therapeutic Drug Monitoring and Clinical
Toxicology (IATDMCT; www.iatdmct.org) as the determination of a
medication’s initial dosing regimen based on patient-specific baseline
information, such as body size, laboratory data, and genetic makeup. In recent
years, significant progress has been made in quantitative pharmacology using