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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
The death of a patient with an inherited metabolic deficiency, Jesse
Gelsinger, in a gene therapy experiment in Philadelphia in September 1999
73
was a catalyst for the formation of a new agency within the Department of
Health and Human Services, the Office for Human Research Protection, in
June 2000.
74
The responsibilities for supervising federally funded research were
previously in the Office of Protection from Research Risks in the NIH. The
Office of Human Research Protection has both enforcement and educational
roles. The FDA published an adaptation of Subpart D of 45 CFR 46 in the
Federal Register in 2001 that would extend the principles and risk categories
of the original regulations with some modification to all FDA-regulated
research and not just federally funded research.
75
The Best Pharmaceuticals for Children Act (BPCA), signed into law in
January 2002, renewed the incentive program contained in the FDAMA and
extended the time for the FDA to issue written requests until October 2007.
Study reports were due whenever the written request stated and were
independent of the last date for issuing written requests. Additionally, the
BPCA in 2002 endorsed the principle of public disclosure of information
regarding the effects of medications in children and provided mechanisms
such as Federal Register notices, posting of FDA review summaries on the
Internet, product labeling, and advisory committee discussion to promote this
goal. A further provision in the BPCA provides mechanisms for the study of
off-patent drugs in pediatric populations and a plan for adverse event tracking
and reporting.
76
The federal pediatric initiatives were renewed, revised, and extended in
September 2007 with enactment of Public Law 110-85, The Food and Drug
and Administration Amendment Act of 2007 (FDAAA). Within FDAAA, Title
IV, The Pediatric Medical Device Safety and Improvement Act; Title V, The
Pediatric Research Equity Act; and Title VI, The BPCA are all directed at
pediatric populations, while Title VIII, Clinical Trial Databases, has
implications for pediatric research through the mandatory listing and posting
of summary results of clinical studies using FDA-regulated products. FDAAA
also established an FDA Pediatric Review Committee.
77
The Pediatric Medical Device Safety and Improvement Act extended the
general principles of pediatric initiatives to medical devices. The definition
of child in that Act for research purposes is up to and including 21 years of
age. The interpretation of the definition is that if other pediatric populations
are enrolled, the upper limit should include patients through 21 years. The law
does not state or imply that a study that enrolls patients between 18 and 21
years is a pediatric study nor that such a study would be responsive to any of
the federal pediatric initiatives. The law recognizes that some studies of
childhood diseases and conditions that enroll patients through 21 years
acknowledge late physiologic and developmental changes at the end of
adolescence and that inclusion of such patients can be scientifically and
medically informative. The primary features of the Pediatric Medical Device
Safety and Improvement Act are:
1. Requirement to perform pediatric studies in relevant populations
2. Applicability of the law to “patients” who “suffer from” a disease or
condition
3. Specific monitoring requirements
4. Funding of demonstration projects
5. Development of a federal pediatric medical device plan
6. Designation of a pediatric medical device point of contact at the NIH
In July 2012, Public Law 112-144, the Food and Drug Administration
Safety and Innovation Act (FDASIA), made the BPCA and the Pediatric
Research Equity Act (PREA) permanent and therefore no longer subject to a
term limited expiration. In Section 508 the law required that every 5 years the
secretary of Health and Human Services report to Congress on various
activities related to Sections 505A and 505B of the Food, Drug, and Cosmetic
Act. Additional provisions include:
Establishment of a permanent position of a neonatologist in the Office of
Pediatric Therapeutics and as a member of the Pediatric Review
Committee
For products granted pediatric exclusivity under the BPCA, in addition
to the medical and clinical pharmacology reviews, a statistical review
be posted
On August 18, 2017, Public Law 115-52, the FDA Reauthorization Act
(FDARA), was signed into law. This included the Research to Accelerate
Cures and Equity (RACE) for Children Act, which requires evaluation of new
molecularly targeted drugs and biologics “intended for the treatment of adult
cancers and directed at a molecular target substantially relevant to the growth
or progression of a pediatric cancer.” It also eliminated the orphan exemption
from pediatric studies for cancer drugs directed at relevant molecular targets.
FDARA permanently authorized the requirement for neonatology expertise in
the Office of Pediatric Therapeutics at the FDA and required the development
of draft guidance on clinical pharmacology considerations for neonatal studies
for drugs and biologics.
78
As of mid-2019, the FDA recorded about 785 labeling changes, of which
715 were based on new pediatric studies. Attributions for which pediatric
initiative supported the label change are PREA alone 430, PREA + BPCA
119, and BPCA alone 187. Another 49 are attributed to the Pediatric Rule. An
inference from these results is that the mandate accounted in whole or in part
for almost 600 label changes. The incentive program accounted in whole or in
part for approximately 300 label changes. The combined programs triggered
new pediatric studies to support 91% of the label changes.
The package insert or label changes include information on pediatric
doses, safety information, and in some cases extended or established
indications for pediatric use.
79
GENERAL SCIENTIFIC AND ETHICAL
RATIONALE FOR CLINICAL STUDIES
For thousands of years medicine relied on tradition and eminence-based
practices, that is, practice based on authority that was not questioned.
Interventions that were thought to be highly active were readily adopted, but
other treatments were promulgated without formal establishment of their
effectiveness. As a result, the history of medicine is populated with practices
that harmed patients and diverted resources. General acceptance that a
demonstration of effectiveness based on scientific principles is a necessity for
marketing authorization and acceptance into clinical practice came in the mid20th century.
The current status of knowledge of biology and pharmacology is
insufficient to allow deduction of therapeutic effects, risk, and clinical
outcome. Empirical observations are necessary to predict potential risks and
benefits, and observations are often limited for technical and psychological
reasons including false expectations, inability to observe events, and bias.
The goals of clinical research are to maximize the validity of the observations
so that they can be generalized to other relevant populations and minimize the
major confounding influences of bias and uncertainty.
Bias is the tendency, intentionally or unintentionally, to influence the
outcome by factors such as the study design or implementation. Uncertainty is
a measure of the confidence in a result. It is defined as the amount that the
apparent result differs from what would be a “true” result. The larger the
uncertainty, the less confidence there is in the apparent result. Even if the
“true” result is not known, there are various analytic methods to determine the
level or degree of uncertainty.
Among the ethical reasons for striving for unbiased research are
minimizing exposure of patients to unjustified risk and avoiding the
consequences of disseminating misleading results, which include not only
unjustified risk, but the potential delay of the development or implementation
of superior alternatives.
For many years, multiple definitions of the terms “clinical research” and
“clinical trial” were published by different organizations, but the NIH
attempted to consolidate the definition of “clinical trial” in 2014. The current
definition is “A research study in which one or more human participants are
prospectively assigned to one or more interventions (which may include
placebo or other control) to evaluate the effects of those interventions on
health-related biomedical or behavioral outcomes”.80 For this discussion, a
clinical trial will be a bit more broadly defined as a systematic investigation
for the evaluation of an intervention regarding potential risks and benefits for
a defined target population or phenotype. The broader definition is more
aligned with international usage of the concept. The linkage to biomedical
outcomes noted in the NIH definition will apply when referencing U.S.
government scientific funding programs to maintain consistency, but for other
discussions, the emphasis will be on the evaluation of the intervention without
specific linkage to meeting a specific definition for the type of outcome.
CONCEPTUAL PARADIGM FOR CLINICAL TRIALS
A clinical trial in an abstract form is an activity designed to capture data to
support solving a problem for a target population. Operationally, a clinical
trial is a series of coordinated encounters where a person, an intervention, a
context, and relevant measurement methods coincide in time and space (Fig.
1.3). The major conceptual differences between a clinical trial encounter and
health care delivery encounter are that in a clinical trial:
The intervention is provided in the context of a protocol.
The intervention is under evaluation.
Participation is voluntary with documented permission.
The data will be pooled and analyzed systematically.
The results will be disseminated.
The clinical trial process has greater stringency and oversight than
standard health care delivery.
Figure 1.3 Conceptual framework for clinical trial data capture with the intersection of the study
participant, the intervention, measurements, and infrastructure and logistics in time and space.
MINIMIZING BIAS AND UNCERTAINTY
Clinical trials should be undertaken with the concept of equipoise, that is, the
expectation that the results are unknown prior to the clinical trial and can only
be known after a clinical trial is properly conducted and analyzed. The
concept of equipoise has multiple interpretations and may vary with
perspective but is generally taken to reflect that the information needed to
make a critical decision is not available and the planned study is intended to
contribute to that information.
81
Among the methods to reduce bias and uncertainty are:
the integration of controls or comparators in the design and analysis to
properly interpret the signals generated by data capture. The most
precise controls or comparators have their data generated concurrent
with the study data, usually by exposing one group of participants to the
intervention under evaluation and exposing another group of participants
to the control or comparator. The control or comparator is typically a
placebo, an alternative intervention, or nothing at all.
selection of measurement techniques and outcomes that are objective,
quantitative, validated for the specific population of interest, and have
characteristics that are well defined and precise over a known range
utilization of qualified and trained personnel with specific training on the
study protocol, techniques, and quality management
a risk-adjusted quality management plan and infrastructure for study
implementation
a data security plan with audit tracking
use of an ontology and terminology that provides the detail and precision
needed to objectively describe the phenotypes and events that will be
captured
82–84
a prospective data analytic plan with potential adjustments in the study
protocol prespecified
a data sharing plan to allow independent access to the data for
confirmation and validation of study-specified analyses
CONSIDERATIONS REGARDING CONTROLS
A controlled clinical trial will have a comparator integrated into the design.
The most precise controls are concurrent with the time frame and context of
the study because data generated at other times or in other contexts, even other
clinical trials, can be skewed or biased due to differences in definitions,
measurement techniques, and general secular trends that affect people in
general and health care delivery and technology. As an example, imaging
techniques continue to evolve and improve so measurements of masses such
as tumors or cysts will vary in precision based on the type of apparatus, the
calibration technique, the version of the analytic software, and the date and
location it was measured. Microbiologic diagnosis will vary based on when,
from where, and what type of processing a sample may have had; the
identification methodology such as morphologic, immunologic, genetic, or
other criteria; and the characteristics and calibration of the equipment.
An important goal of any scientific study is to reduce the number of
variables that can affect the outcome to a minimum. Using concurrent controls
that employ the same methodology with personnel trained in the same way and
risk-adjusted quality management are among the most effective and pragmatic
approaches to minimize variability in data capture.
RANDOMIZED CONTROLLED TRIALS
Randomized controlled clinical trials, where individual participants were
assigned to receive either an intervention to be evaluated or a comparator,
were developed in the United States and the United Kingdom during the 1920s
and 1930s, but Dr. Austin Bradford Hill initiated the practice of using random
numbers to assign patients to treatment arms to study infectious disease
therapy, which grew out of a need to treat malaria during World War II.
85
In 1948 the Medical Research Council of Britain reported on the use of
streptomycin to treat pulmonary tuberculosis in a randomized controlled
trial.86 Following World War II, randomized controlled studies began in the
United States in academia with a study at Johns Hopkins University
comparing tetracycline to penicillin for the treatment of pneumococcal
pneumonia and in government with the Veterans Administration study of
tuberculosis.
87,88
The first randomized controlled pediatric study, as noted previously, was
organized by the U.S. NIH as a multicenter trial for rheumatic heart disease in
1951.
89
In 1954, Congress established the Cancer Chemotherapy National Service
Center (CCNSC). Subsequently a clinical trial network was initiated with one
section devoted to pediatrics. In the establishment of the clinical program, the
CCNSC agreed upon the importance of the following principles:
1. Combination of data from all institutions to rapidly accumulate the
necessary number of patients
2. Standard criteria of diagnosis, treatment, and measurement of effect
3. Statistical design of the study with randomly assigned patients to
different treatment groups
4. Statistical analysis and collaborative reporting of results
The rationale for these principles was that randomized studies generally
provide more persuasive evidence of benefit than alternative study designs
such as single-arm studies. Improvements in outcomes ascribed to treatment
may be due to other factors such as patient selection (selection bias), other
medications or therapies, diet, genetics, and other environmental factors. In
addition, historical control populations may differ from current study
populations regarding demographics, precision of diagnosis, and changes in
the general practice of medicine.
90,91
The design and analysis of clinical trials continue to evolve, but the value
of careful observation and recording of results is timeless. Independent of
trial design, clinical studies must address ethical requirements. The varied
published international documents have overlapping characteristics and
elements, and these have been analyzed by Emanuel, Wendler, and Grady of
the NIH, leading to a recommendation of seven requirements for ethically
conducting a clinical study. They are value, scientific validity, fair subject
selection, favorable risk–benefit ratio, independent review, informed consent,
and respect.92 Regarding children, the issue of informed consent, as
previously discussed, is redirected to parental or guardian permission and
assent.
SPECIFIC RATIONALE FOR CLINICAL
STUDIES IN CHILDREN
One of the prevalent justifications for studying interventions in children is that
children are not small adults. Indeed, results of studies in one adult population
may not be translatable to another adult population. The differences between
TABLE 1.2
children and adults are many and vary according to age and developmental
stage. Examples are listed in Table 1.2.
Factors That Vary With Age and Deve lopmental Age
Continuing changes in physiologic development and metabolic function such as renal and hepatic
function
Evolving surface-to-volume ratio
Changes in integrity of the skin and other anatomic barriers
Alterations in penetrability of the central nervous system barriers
Maturation of the neurohumoral-immune axis
Alterations in protein binding and displacement
Continuing anatomic changes such as skull shape, size, and proportion of passages such as eustachian
tubes, mineralization of cartilage, structure and location of lymphatic organs including the thymus
The continuing metabolic changes and alterations in surface-to-volume
ratio, lymphatic structure and function, and other anatomic and physiologic
factors limit the use of fixed doses in children and are the basis for the need to
study dosing in people of different sizes and developmental stages. Among the
reasons are the increased risk of adverse reactions or decreased effectiveness
due to inappropriate dose and the potential reluctance of practitioners to
prescribe potentially useful products without adequate information.
Additional general factors to address in pediatric studies are the sampling
challenges of obtaining meaningful clinical material such as blood, serum,
tissue, and images in patients of various sizes; degrees of maturation; and
developmental stages.
93
The AAP issued updated Guidelines for the Ethical Conduct of Studies to
Evaluate Drugs in the Pediatric Population in 1995, which can be summarized
as follows66:
The premise of studying drugs in children is that it is ethically imperative
so that children can have equal access to therapeutic agents. In most cases,
therapeutic agents should be studied in adults prior to children except for
agents that are specific for pediatric diseases. Proposed pediatric research
must by design protect children and encompass six conditions:
The proposed research must be of value to children in general and, in
most instances, to the individual child subject. The value may be a
potential benefit in the treatment of the subject’s disease or may be
improved understanding of basic biology of the disease state or of
children in general.
The research design must be appropriate for the stated purposes. Poorly
designed research may not provide scientifically valid or useful data and
may place the subjects at risk with no potential benefits.
The research design must take into consideration the unique physiology,
psychology, and pharmacology of children and their special needs and
requirements as research subjects.
The design should minimize risk while maximizing potential benefit.
The study design must take into account the racial, ethnic, gender, and
socioeconomic characteristics of the children and their parents and,
when appropriate, should include input from the community or
appropriate advocacy representatives.
The study must be designed to conform to the local, state, and federal
laws of the jurisdiction of the study’s location and the investigators’
home jurisdiction, and to their local and national ethical guidelines.
The document further states that research studies may be considered
ethically permissible when they can be shown to have a potential benefit to
the individual child or provide generalizable knowledge, and when potential
benefits outweigh potential risks. Benefits should be construed broadly. The
investigator’s competence and ethical conduct are the most important
safeguards for the protection of the child. The primary responsibility of the
IRB is to protect the rights of the research participant.
Additional subsections address specific populations that may be at
increased risk for abuse and exploitation, including the child with handicaps,
institutionalized children, patients requiring emergency care, the dying patient,
patients with chronically progressive or potentially fatal disease, and the