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TABLE 1.6
contains an analytic plan that minimizes bias and uncertainty. Some elements
to address in trial design and protocol writing are listed in Table 1.6.
Trial De s ign Ele ments
Element Comment
TIME FRAME
Prospective A protocol is written and the study is performed following the
approval of the protocol. Opportunity to collect all data that are
required to test the hypothesis.
Retrospective A protocol is written to systematically analyze historical data. Often
unable to locate all the data required to test the hypothesis.
CONTROLS
Historical Comparison is made with either a specific study that is considered to
be an appropriate match for the current therapy or with a valid metaanalysis of a series of previous studies. Major problems are:
1. Changes in medical practice (secular effect) that affect results
over time
2. Differences in eligibility criteria in different protocols
3. Differences in assessment in different studies
4. Differences in analysis in different studies
PLACEBO
Supportive care If no active therapy exists for the patient population then it may be
ethical to provide supportive care plus a placebo vs. supportive care
plus the test therapy. Examples may include testing a symptom benefit
therapy.
Add-on All arms receive the same standard therapy with the control arm
receiving in addition a placebo and the experimental arm receiving in
addition the test therapy.
ACTIVE
Standard therapy Direct comparison between a standard therapy and the test therapy.
Add-on All arms receive the same standard therapy with the experimental
arm receiving in addition the test therapy.
Withdrawal All arms receive the same therapy until a predetermined time when
one arm has the test therapy withdrawn. The endpoint of interest is
usually the appearance of an event that would be prevented if the test
therapy were still present. This type of design is often used in
measuring the effect of lowering blood pressure.
Dose comparison Different doses of the same drug are compared. Generally a trend in
benefit or response that follows the exposure to the drug is considered
evidence of activity—the greater the exposure the greater the
response.
ARMS
Single A single series of patients
Multiple Treatment arms are compared concurrently to one another.
Crossover Patients can change from one treatment arm to another based on
predetermined criteria. If the critical evaluation occurs after the
crossover it may be difficult to interpret due to factors such as the
sequence of therapy having an effect or one therapy having a delayed
effect.
ANALYSES
Single Study analysis occurs when either a particular time or predefined
landmark is reached.
Multiple Study analysis will incorporate one or more interim analyses triggered
by events, landmarks, or time schedule.
Adaptive The study design may alter in a prospectively defined manner based
on the outcome of an interim analysis; e.g., a study arm may be
closed to accrual, the overall sample size may be increased, or a new
study arm may open. All adaptive designs are based on rules
described in detail in the original protocol and are not based on
protocol amendments developed subsequent to any data analysis.
A protocol must be approved by an IRB and, if an investigational agent is
used or if an FDA-approved product is used under some conditions, then an
IND application must be filed and the protocol reviewed by the FDA.
Detailed information can be found at:
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/
InvestigationalNewDrugINDorDeviceExemptionIDEProcess/default.htm.
There are many possible and plausible design variations that include
having multiple stages where continuation of the trial from an early to a later
stage is dependent on interim results.
Such an approach is termed an adaptive design. Among the more common
is a two-stage design for clinical activity where an initial cohort of patients is
assessed with prespecified rules for a minimum level of activity to justify an
expansion of the study to enroll more patients. Another variation on an
adaptive design would assign subsequent interventions or observations to
patients depending on the results of the initial intervention or other events.
Some study designs are not intended to assess a specific intervention but
are intended to systematically collect data in a prospective manner to
describe natural history or make long-term observations. Such a study design
may be applicable as a follow-up study to a study that assessed an
intervention.
A study design that emerged during the last decade called the “wedgestep” is a variation on a randomized controlled study where multiple arms are
constructed, with each arm having a run-in period of different lengths prior to
exposure to the experimental intervention. The rationale of such a design is to
collectively generate enough time in enough people without the intervention
exposure to serve as a control dataset yet ensure that everyone in the study is
exposed to the intervention.
150–152
CLINICAL TRIAL MONITORING
The risks of investigational therapy can be unknown. Extrapolation from
preclinical models for safety are about 65% predictive.
153
The predictive
value of preclinical models for children is a field under development.
Although preclinical models for teratogenicity exist, several acceptable
preclinical models for pediatric-specific toxicities such as the impact on
growth and organ maturation are still being developed.
In addition, children, particularly the youngest, may not be able to
communicate adverse effects. As a consequence, the monitoring of clinical
studies in children merits greater vigilance than monitoring in adult
populations.
70,84,153–158
The rationale for monitoring is based on two general research principles:
Ensuring and enhancing the safety of the study, that is, to protect the study
participant from unacceptable risk; and
Assuring the scientific validity of the study, that is, to protect the data and
preserve its integrity.
The most critical component is investigator integrity, which can be
actualized by a proactive, comprehensive, and integrated monitoring plan.
To uphold and implement these principles, a monitoring plan must:
Be proactive and anticipate a range of outcomes and responses; and
Include a communication plan to support dynamic interaction between
relevant parties, including monitors, investigators, sponsors, regulatory
authorities, and others.
Monitoring is assuming responsibility for reviewing events and outcomes
during the implementation of a study in two domains: (1) safety of participants
and (2) integrity and quality of data including study accrual. Study monitoring
encompasses comparing events and outcomes to predefined criteria. If the
study events and outcomes indicate deviance from those criteria, study
monitoring would mandate making a recommendation to alter the study
implementation.
Routine monitoring is when the study team has primary responsibility for
monitoring the study typically based on a monitoring plan incorporated in the
study protocol or study plan; IRB oversight; institutional oversight in
compliance with applicable institutional, state, and federal guidelines,
policies, regulations, and laws.
Each study should develop a monitoring plan that is included in the
overall study plan or protocol that defines:
How the study will comply with regulatory requirements
The specific events and activities that will be monitored
The roles and responsibilities for everyone on the team who is involved
in monitoring
Who has responsibility for reporting (and who they report to)
A schedule for monitoring
Any escape and stopping rules
Escape rules are criteria for an individual patient to leave the study based
on disease progression, toxicity, or lack of efficacy. Escape rules may define
alternative regimens. Stopping rules are criteria for either halting accrual or
closing a study for toxicity, lack of efficacy, or sufficient efficacy that further
enrollment is not required to determine a conclusion. If applicable, the type
and number of events that would halt accrual and would generate a review of
eligibility, monitoring, assessments, intervention, and how the resumption of
accrual would occur in each study plan or protocol will include a list of
expected adverse events regardless of whether these adverse events are
referenced or explained in other types of study documentation.
A list or description of expected events should be in the following forms:
A description of the scope of expected adverse events of the underlying
condition based on either a recent literature review or textbook. If none
are expected during the study time frame, simply state that no adverse
events are expected;
If interventional products are administered, a description of the safety
profile for each product administered in the study (investigational and
marketed) including, if known, the frequency, severity, and duration of
adverse events;
If assessments (e.g., a blood test, imaging study, survey instrument) that
are not part of the routine care of the disease or underlying condition are
scheduled in the study, then the known risks and complications from
those assessments should be listed in the study protocol.
The best quality information to include in the study protocol regarding
research-specific assessments would be individual institutional experience
using the assessment at the study site, which includes the total number of
people that received the assessment plus the complication rates. If
institutional experience is not available, published data from similar studies
and published data on the general use of the assessment tool or technique may
be substituted.
An integrated listing of adverse events containing those anticipated from
the natural history plus those anticipated from any and all interventions and
assessments that may occur on study should conclude the anticipated risks
section of the study plan or protocol. The potential advantages of an integrated
list of expected events are that IRBs could readily assess the overall risks
from a study, the informed consent process and documents could be prepared
to better inform prospective study participants of potential risks, and adverse
event reporting could be simplified by comparison of an event with a single
source document.
Risk-adjusted supplemental monitoring can be implemented in addition to
routine monitoring, and depending on the nature of the research, monitoring
can be effectively augmented through mechanisms and independent external
entities such as a single-person Medical Monitor, a small Study Monitoring
Committee, a multidisciplinary committee, or a chartered multidisciplinary
team such as an Independent Data Monitoring Committee (IDMC). Alternative
terms include Data and Safety Monitoring Board, Data Monitoring Board, or
Data Monitoring Committee.
Study characteristics that have risks that can trigger supplemental
monitoring include, but are not limited to:
Late phase clinical trials statistically powered to establish efficacy. Late
phase clinical trials are generally large studies, but not necessarily so,
and are designed to affect current medical practice, product labeling if
applicable, or public health policy.
Multisite/multicenter clinical trials. Multisite/multicenter clinical trials
involve separate institutions using the same study protocol. Several sites
that are within the same legally established institution are not generally
considered to be a multisite study.
Clinical trials involving randomized treatments. Multiarm clinical trials
that use randomization are designed to minimize potential bias in the
interpretation of the results. Randomization implies scrupulous attention
to the details of study implementation to avoid any compromise in data
integrity.
Clinical trials involving vulnerable populations, such as those who are
children, elderly and ill, terminally ill, or of diminished mental capacity,
or any population otherwise unable or unlikely to provide informed
consent that are at greater than minimal risk. If the clinical trial involves
only minimal risk to participants, as defined by 45 CFR Subpart A, Sec.
46.102 and minimal risk to data integrity and quality (e.g., small number
of sites, small sample size, few data elements, short duration),
monitoring can be accomplished through alternative mechanisms, such as
the use of a detailed monitoring plan in the protocol.
Clinical trials in which the treatment is particularly invasive or has other
serious safety concerns that may result in serious toxicity.
Clinical research studies in which an assessment that is used solely for
research purposes is considered greater than minimal risk.
Clinical research studies, including observational studies in which
participants are already at elevated risk of: (1) death; (2) life-threatening
conditions (i.e., immediate risk of death); (3) in-patient hospitalization
or prolongation of existing hospitalization; (4) persistent or significant
disability/incapacity; or (5) congenital anomaly or birth defect. These
events are considered serious adverse events by regulatory authorities.
A clinical research project that is of sufficiently long duration that
protocol changes may need to be considered based on changing medical
practice or interim analyses.
Any clinical trial in which members of the study team have a stated or
perceived conflict of interest.
An IDMC is a structured multidisciplinary mechanism for supplemental
monitoring that may be dedicated to a single study or may serve multiple
studies. The role of the Board or Committee is established before a clinical
trial begins. Its functions typically include review of the protocol before it is
implemented, review of study implementation and progress, and ongoing
review of the accumulating data to detect evidence of early, significant benefit
or harm for participants while the trial is in progress. This latter review
serves as an additional protection for participants, beyond that provided by
the IRB, but does not take the place of regulatory requirements for
investigators to report serious and unanticipated adverse events to the FDA.
Examples of IDMC responsibilities are:
Review the research protocol, review model informed consent
documents, and plans for data and safety monitoring, including all
proposed revisions.
Review methodology used to help maintain the confidentiality of the
study data and the results of monitoring by reviewing procedures put in
place by investigators to ensure confidentiality.
Monitor study design, procedures, and events that will maximize the
safety of the study participants and minimize the risks.
Evaluate the progress of the study, including periodic assessments of
data quality and timeliness, participant recruitment, accrual and
retention, participant risk versus benefit, performance of the study
site(s), and other factors that may affect the study outcome.
Consider factors external to the study when relevant information
becomes available, such as scientific or therapeutic developments that
may have an impact on the safety of the participants or the ethics of the
studies.
Review serious adverse event documentation and safety reports and
make recommendations regarding protection of the safety of the study
participants.
Report on the safety and progress of the study.
Evaluate and report on any perceived problems with study conduct,
enrollment, sample size, and/or data collection.
Provide a recommendation regarding continuation, termination, or other
modifications of the study based on the cumulative experience including
the observed beneficial or adverse effects.
An IDMC operates under a charter outlining the roles, responsibilities, and
standard operating procedures for the group. The charter will:
Define the roles, responsibilities, and relationships for each of the
members, such as who are voting members or advisory members, who
may attend open and closed sessions, the line of authority for reviews
and decision making, who is granted access to certain data (e.g., blinded
and unblinded), the compensation for IDMC members, and any potential
conflicts of interest.
Outline the responsibilities of the group including: familiarizing group
members with the study protocol and monitoring of adverse events, data
quality, participant recruitment and enrollment, the risks and benefits,
reporting, etc.
May also include an organizational chart depicting the relationships
between all of the major stakeholders of the study team, the study
sponsor, the funding organization, and the IDMC.
Identify the standard procedures for each items such as meeting
frequency and format, including logistics and required attendees/quorum,
procedures for unscheduled evaluations, including types of events that
would trigger an unscheduled evaluation, expected information,
involvement of the study chair, required number of members, and
communication of recommendations.
Identify statistical procedures that may be utilized by the IDMC,
including any stopping rules based on benefit or harm, futility analysis,
or decision points in adaptive designs.
Monitor recruitment goals.
Identify methods for making recommendations to the study sponsor and
investigators, funding organization, and other relevant parties.
INTERNATIONAL STUDIES
Performing a study in several countries could have multiple advantages
including faster accrual, potentially greater confidence in the results due to
replicability, and sharing of resources. Engagement in international studies
could also provide opportunities for professional development and
cooperation as well as support better acceptance of study findings. In
addition, best practices could be disseminated based on the clinical trial
experience, which would quickly and directly benefit pediatric patients. The
implementation of international studies, to be informative for all participants,
should meet several criteria. The study question should be of value to all
communities that participate. All assessment techniques should be available
and validated at all sites. Eligibility criteria should be standardized. The data
repository and analysis should be centralized.
Among the considerations in the design and implementation of an
international study are the types of diseases relevant to each region, priority
of any new proposed agents, types of studies, and incorporation of study
endpoints that are demonstrative or predictive of clinical benefit. There are
also several barriers that include, but are not limited to, regional differences
in health care systems and practice, lack of common informatics standards,
different languages and different medical terms, logistics and speed of
protocol development, regulatory requirements and inconsistencies,
compliance with good clinical practice and assurances, logistical challenges
to sample processing, access to new agents, data sharing and credit, and
funding.
158
Cooperative and collaborative studies in the 21st century will be feasible
on the basis of development and acceptance of international standards for data
acquisition, data transmission, and adherence to infrastructure and systems
that are interoperable as a result of standards.
145,159–161
COMPLEXITIES OF CLINICAL TRIAL
IMPLEMENTATION
Clinical trials have a life cycle with a repetitive series of activities that can
be summarized as
Submission of a structured document for peer review evaluation
Evaluation of the document based on established criteria
Response to evaluation
If the evaluation is favorable, the clinical trial process proceeds to the
next step, often with some modification.
Examples of steps in the life cycle process include funding review,
scientific review, human subject protection review, FDA review, data
monitoring committee review, funding agency review, and publication review.
The process has multiple steps and each review focuses on different
criteria.