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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Examples of the types of questions and subsequent actions to be taken
include a formal determination of whether the activity is research, if it is
human subject research, if IRB review is required, what type of IRB review
may be required, classification if the activity is funded by the US NIH, IND
requirement if an FDA-regulated product is used, and expectations regarding
the informed consent process.
Figure 1.8 outlines in schematic form one feasible sequence of decisions
to approach the multiple decisions.
Figure 1.8 Integrated clinical research flowchart.
COMMON WEAKNESSES OR ERRORS IN
TRIAL DESIGN OR ANALYSIS
It is rare for a pediatric study to enroll large numbers of patients outside
vaccine trials, so designs and analytic plans must anticipate a limited patient
population size. Techniques are available to address the problems associated
with limited population size.
162
Hayden and colleagues noted a trend over the prior 30 years of pediatric
research to increasingly use a variety of statistical techniques and offered a
critique of published studies.
163
Pocock later published a survey of statistical
problems in clinical trials that noted that studies tended to have excessive
hypothesis testing, which increased the number of false-positive findings.
164
An FDA survey in 1999 noted several consistent weaknesses in
submissions of clinical trial data for review. These included invalid
assumptions, analytic methods, incomplete data, no dictionary for data fields,
absence of a protocol with the submission, no statistical plan stated in the
protocol, incomplete submissions of data, inconsistent field names across
studies, multiple terms for the same type of adverse event, unexplained
dropouts, lack of follow-up, treating categorical data as continuous data,
mixing dose exposure and dose response, inventing new response variables,
unspecified subgroup analysis, analyzing only “evaluable” patients displaying
only adjusted analyses, stating results as percentage change or percentage
change in hazard ratio, site bias, expressing efficacy per patient and adverse
events per dose, and pooling analyses of distinct patient populations.
165
Given
the preciousness of the resource of pediatric patients, it is imperative that
studies be informative and include an analytic plan that minimizes
assumptions, is consistent with the endpoints, adheres to accepted statistical
principles, and is prospective.
CONCLUSION
On an abstract level, health care delivery is based on the principle of an
information flow that integrates general and specific information to support a
decision intended to benefit a patient. While some of the information comes
from direct observation including a history and physical findings, and some
comes from real- or near-time assessments such as images or laboratory
studies, guidance is provided by upstream sources such as cumulative
experience and research data.
A system schema of the information flow is outlined in Figure 1.9
illustrating the linkages between the health care delivery system and the
clinical research system.
Figure 1.9 Linkages between health care delivery and research. The flow of information is in black.
The transition of individuals is in blue. Permission is a generic term to indicate either consent from
individuals legally capable of providing consent or the permission process by a parent or legal guardian or
authorized representative to provide permission for an individual to participate in research. The
permission process may or may not include an assent component.
Within the research process, a similar abstraction of a study, whether it
involves primary data collection or not, is the need to produce a quality
analytic dataset.
From both an abstract and a practical perspective, the goal of any research
activity is to produce inferences that support decision making. The general
method is to assemble either previously collected or capture de novo primary
data to construct analytic datasets. Primary means line level or patient level
or participant level, as in this context these terms indicate the same concept.
The quality and stringency of the primary data determine the quality,
stringency, and robustness of the analytic dataset. High-quality, highstringency primary data can be used multiple times and contribute to multiple
analyses to address questions of interest and relevance. Once an analytic
dataset is properly constructed, that dataset can be used to produce inferences
with estimates of confidence around the inferences. The inferences in turn are
used to support decision making, whether it is a sponsor deciding on the next
step in a development program or describing a use claim for a regulatory
submission, a regulator making a determination if a use claim is adequately
supported with regard to benefit and acceptable risk, or a practitioner
selecting an intervention for a patient. There are many other examples, but the
general paradigm holds (Fig. 1.10).
Figure 1.10 Terminal stages of research process showing the flow from data collection to decision
support.
For historical and practical reasons, the need for high-quality, highstringency data to support the use of medicinal products in children is an
imbalance between need and supply.
A key distinction between research decisions and health care decisions is
that research addresses populations, while health care delivery addresses
individuals. An analogy may be between classical quantum mechanics as
described by Schrödinger, which is directed at system states, and quantum
trajectory theory, which is directed at individual particle states. To invoke
quantum trajectory theory, near complete system information is required,
which is now feasible with sufficient precision to permit the relevant
calculations. Classical quantum mechanics is not intended or capable of
predicting individual particle states and trajectories.
In the case of human physiology and the contextual influences on the most
probable responses for an individual, we do not have the knowledge or the
assessment tools to predict the probable response with a high level of
precision. Thus, research results can support decision making but are not
expected to inform the trajectory of the status of an individual.
What research results can support are population results regarding health
care and specific results within the research system for the trajectory of a
research project. Examples include Go–No Go decisions. Contexts for Go–
No Go decisions include:
Issuing licenses where passing a test results in receiving the license,
whereas not passing the test results in no license.
FDA approval for a product use claim where establishing efficacy that
can be reasonably mapped to clinical benefit and providing sufficient
evidence to infer an acceptable safety profile can result in marketing
authorization. Failing to establish efficacy results in no approval.
Establishing efficacy without an acceptable safety profile also results in
no approval.
A Master Protocol will continue to enroll study participants on each arm
until an arm meets criteria for discontinuation.
Multiple applications within a cohort are submitted for a funding review
with only a subset selected for funding.
Multiple product candidates under development are evaluated for
continuation to the next stage of development.
The common factor is that criteria are established to guide the decision
making and research data provide the enabling information to make the
assessment.
Scientific and ethical rationales support the use of clinical investigations
to minimize risk and maximize benefit for the use of therapeutic products or
interventions. Children of various ages have sufficient differences in
metabolism, organ maturation and function, emotional and psychological
function that studies are necessary to extend the benefits of therapeutics while
minimizing the potential for harm.
Clinical studies in pediatric patients should be designed to minimize risk,
distress, and discomfort. This is best done by trained and experienced
pediatric investigators at facilities that can support the special needs of
pediatric patients and by adherence to accepted principles of patient
protection and respect for persons. Enrolling children in studies is a
combination of educating and gaining the permission of parents or legal
guardians and educating the child while obtaining assent if appropriate.
There are conditions when the permission/assent process can be
postponed or waived due to emergent circumstances. Approaches to minimize
nontherapeutic interventions such as sparse population sampling for
pharmacokinetics and special imaging studies in lieu of tissue sampling are
preferred. Study design should incorporate escape rules for individual
patients, stopping rules for the entire population, and an IDMC, if appropriate,
particularly for life-threatening diseases. Assessments, both clinical and
laboratory, need to be age and developmental stage appropriate. Multiple
factors may affect study results. Patient-reported outcomes are generally not
sufficiently reliable to serve as the only endpoint and should be confirmed by
other objective findings. Strategies to minimize exposure and risk include
studying older populations before younger ones and using extrapolation of
efficacy when scientific evidence warrants.
Diseases or conditions that are specific to a particular age group require
studies in that population. Study designs and analytic approaches need to
address the limitations of small numbers of patients and variability among
patient populations. International cooperation can share resources but has
many challenges to address before multinational pediatric studies become
routine (Fig. 1.11).
1.
2.
3.
4.
Figure 1.11 Integrated activities to support pediatric research showing how resources, policies,
culture, and training intersect to produce quality data.
Clinical studies in pediatric patients are a necessary component of
therapeutic development unless the product is unsafe or addresses only a
condition that does not exist in children. The responsibility for clinical studies
in pediatrics is shared with pharmaceutical firms, regulatory authorities,
health professionals, and society as a whole. The most vulnerable populations
merit the most protection and deserve the benefits available to others, which
is achieved through careful and persistent pursuit of further knowledge.
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