Page 366 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

344 PART III Therapeutic Modalities for the Cancer Patient

of missing an association of a given effect if it exists. This repre- practice (GMP) and good clinical practice (GCP). GMP prin-
sents a power of 0.90 (1 – β), or a 90% chance of finding an asso- ciples ensure the safe manufacture and testing of pharmaceuti-
cal drugs, biologics, and medical devices by outlining aspects of
ciation of that size or greater. The α and β levels are determined
VetBooks.ir before trial initiation, and their set points are based on the impor- production that can affect the quality of a product. GCP guide-
lines were devised by the International Conference on Harmoni-
tance of avoiding either a false-positive or a false-negative result.
Randomization zation (ICH) to protect the rights and safety of human patients
in clinical trials.
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Bias is introduced error in clinical research. One of the main ways GCP includes standards on how clinical trials should be
to minimize bias is through the use of randomization, wherein designed and conducted, defines the roles and responsibilities of
research participants are assigned to a group within a clinical trial trial sponsors and clinical research investigators, and monitors
1
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by chance instead of choice. Groups include either the investiga- the reporting of trial data. It requires the use of a standard-
tional group, those to receive the study drug, or the control group, ized clinical protocol and strict documentation of procedures
those to receive a placebo (or comparator drug). Each participant and adherence to that protocol. GCP also establishes guidelines
enrolling in a trial has an equal chance of receiving the study drug, for oversight by external bodies, such as the Institutional Review
and the goal is to balance the groups based on participant charac- Board (IRB) and the Data Safety and Monitoring Board (DSMB).
teristics (e.g., age, stage of disease, previous treatments) that may The IRB serves as an independent ethics committee that has the
influence a response to therapy. At the end of the study, if bias is power to approve, disapprove, or ask for modifications to planned
reduced by randomization, then the result (positive or negative) is study protocols. IRBs must include at least one nonscientist and
more likely to be true. Unfortunately, in veterinary medicine, his- a noninstitutional member known as a community member. If a
torical rather than active controls have been used for comparison clinical trial includes a vulnerable population, then the IRB must
of new therapies all too often. It is common in oncology trials to include an expert in the needs and specialties of this group. The
also blind participants so that patients or, in our case, clients do IRB reviews protocol ethics, informed consent, and possible con-
not know which treatment group their pet is in. Blinded or true flicts of interest, and provides scientific review of study protocol
active comparator trials are becoming more frequent as regulatory and results.
registration trials ultimately require them. The DSMB (sometimes called a Data Monitoring Committee)
Reducing bias in clinical trials is an integral concept within trial is a third-party panel of experts consisting of at least one statisti-
design. Stratification is a concept used often in human oncology cian, and is populated by clinicians who are experts in the field of
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trials and is gaining headway in veterinary oncology trial design research or drug of study. In long-term and high-impact studies,
as well. 45,51 This allows for grouping of patients based on known an ethicist and/or a patient advocate representative may also serve
prognostic factors. For example, this might include the stratifica- on the DSMB. The purpose of the DSMB is to ensure the safety
tion of dogs with lymphoma by clinical stage or immunopheno- of participants through oversight and management of serious AEs
type with the goal of creating equal numbers of each within a (SAE). This group also ensures validity of data, and appropriate
treatment group. One of the main benefits of stratification is that termination of studies for which significant benefits or risks have
it can prevent potential bias from known prognostic factors. For been uncovered or if it appears that the trial cannot be concluded
example, a treatment cohort may be doing comparatively poorly successfully. However, the DSMB also reviews interim study
because the majority of dogs in that cohort had T-cell lymphoma. results to determine whether an overwhelming benefit is evident
However, a difficulty with stratification is that the more prognos- in either the study or the control arm or if it is unlikely the study
tic factors are controlled, the less power the study has, and thus the will answer the proposed study aim and thus should be termi-
need to increase sample size. Randomization to treatment groups nated prematurely. It is important for all safety monitoring to be
should be performed after stratification. contemporaneous, including disclosure to the FDA of SAEs in
real time. GCP compliance is necessary for FDA registration tri-
Phase IV Trials (Postregistration Trials) als in both veterinary and human oncology drug development.
Oversight of GMP and GCP provisions are provided by the FDA
Once a drug has been granted a license or registered for a spe- (http://www.fda.gov) and, in the European Union, oversight is
cific label use by the appropriate regulatory body (e.g., the FDA), provided by the European Medicines Agency (EMA; http://www.
postregistration phase IV trials may be performed to gain more ema.europa.eu).
information on AEs, long-term risks, off-label benefits, and the
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economic effect of the agent in the marketplace. Phase IV trials Effectiveness versus Efficacy Definitions
may also involve treatment of special populations (e.g., the elderly, A key distinction in phase III trials is that data may be obtained
pediatric patients, or individuals with renal or hepatic dysfunc- within the context of randomized clinical trials (RCTs) or from
tion). The body of data on PK generated from postregistration effectiveness studies in the “real world.” Because RCTs are
trials is used to inform decisions on dose in special populations. designed to assess safety and efficacy of pharmaceuticals with an
Alternatively, phase IV trials may assess the benefit of the new drug emphasis on study validity over generalizability, the applicability
for activity against diseases not included in the current approved of data collected from them may be limited. The data may not
regulatory label. be valid in more heterogeneous patients encountered in actual
clinical practice and may be inaccurate because of strict protocol
Good Manufacturing Practice/Good Clinical requirements or inclusion/exclusion criteria. Effectiveness studies,
Practice Criteria in which treatments are studied under real-world conditions, rem-
Provisions that create uniformity and consistency are key in clin- edy some of these limitations. An efficacy study asks the question,
ical research implementation. Their primary intent is to ensure “Does the drug work?” Whereas an effectiveness study asks the
the safety of trial materials and participants and the integrity question “Does the drug help the targeted general population?”
of clinical data. Such provisions determine good manufacturing Some refer to this efficacy research as type I research (bench to