CLINICAL TRIALS

Overview
• Introduction
• History
• Different types of Clinical trials and their phases
• Clinical Trial – basic considerations
• Design of a Clinical Trial
• Conduct and reporting
• Recent Approaches
 INTRODUCTION
• Clinical trial is a prospective study that includes an active
intervention, carried out in a well-defined patient cohort and
producing interpretable information about the action of the
intervention.
• Clinical trials enable physicians to advance medical care in a safe,
scientific, and ethical manner.
HISTORY OF CLINICAL TRIAL DESIGN AND
IMPLEMENTATION
• 1747—James Lind’s work on the effect of citrus fruits in the prevention of scurvy
among sailors in the Royal Navy
• 1863—Austin Flint’s use of a placebo group for comparison with an experimental
treatment in the treatment of rheumatic fever
• 1947—Nuremberg Code, a result of the appreciation that much of the medical
experimentation performed by physicians in Nazi Germany was both ethically
wrong and scientifically uninterpretable
• 1948—The first double blind trial, performed by the British Medical Research
Council to assess the value of streptomycin in the treatment of tuberculosis
• 1964—Declaration of Helsinki developed by the World Medical Association,
ethical guidelines, which continue to be updated, for the performance of clinical
trials
• 2000—Creation of the ClinicalTrials.gov Web site, a registry of clinical trials under
the National Institutes of Health (NIH)
 THE THREE IMPORTANT KEY WORDS

Experimental Unit
used to specify the intended study population to which the results of the
study are inferred.
Treatment
can be a placebo or any combinations of a new pharmaceutical identity (e.g., a
compound or drug), a new diet, a surgical procedure, a diagnostic test, a medial
device, a health education program.

Evaluation
of effectiveness and safety of a test treatment, clinical trials are also designed
to assess quality of life, pharmacogenomics, and pharmacoeconomics
associated with the treatment under study.

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 DIFFERENT TYPES OF CLINICAL TRIALS

• Treatment trials test experimental treatments, new combinations of drugs, or new approaches to
surgery or radiation therapy.

• Prevention trials look for better ways to prevent disease in people who have never had the disease
or to prevent a disease from returning. These approaches may include medicines, vaccines,
vitamins, minerals, or lifestyle changes.

• Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular
disease or condition. Diagnostic trials usually include people who have signs or symptoms of the
disease or condition being studied.

• Screening (Early detection) trials test the best way to detect certain diseases or health
conditions.

• Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the
quality of life for individuals with a chronic illness. 6
 DIFFERENT PHASES OF CLINICAL TRIALS
• PRE-CLINICAL PHASE –
• It involves in vitro (test tube or cell culture) and in vivo (animal)
experiments using wide- ranging doses of the study drug to
obtain preliminary efficacy, toxicity and pharmacokinetic
information.
• Such tests assist pharmaceutical companies to decide whether
a drug has scientific merit for further development as an
investigational new drug (IND).
 PHASE I - HUMAN PHARMACOLOGY
• 20-50 subjects, 1 year
• Healthy volunteers or volunteer patients, according to the class of
drug and its safety.
• Objectives:
• Pharmacokinetics (absorption, distribution, metabolism, excretion).
• Pharmacodynamics (biological effects) tolerability, safety, efficacy.
PHASE I
• Main objective - to determine the maximum tolerable dose (MTD) of
an agent to be subsequently used in testing for efficacy.
• This concept has been adapted to test radiation alone and combined
drug/radiation regimens.
• The basic conceptual approach is that of sequential dose increases,
until the treatment-related adverse event rate reaches a
predetermined level or unexpected toxicity is seen.
PHASE I
• Parameters to be defined at the outset –
• Patient eligibility criteria,
• Starting dose and
• Schedule of dose escalation
• Events comprising the adverse event/toxicity response
• The expected maximum tolerable dose
 PHASE II - THERAPEUTIC EXPLORATION
• 50-300 subjects, 2-3years
• Patients.
• Trials with inclusion and exclusion criteria
• Primary and surrogate end points
• Objectives:
• Pharmacokinetics and pharmacodynamic dose-ranging
• Therapeutic efficacy
• Phase 2a/ Early Phase • Phase 2b/ Late Phase

• 200 patients • 400 patients

• Single blind • Double blind

• Potential therapeutic benefits • Potential therapeutic benefits
and side effects and side effects
PHASE II
• Purpose - to determine the response rate of the treatment, to gather
more robust adverse event information at the established dose.
• End point of the phase II trial –
• tumor response
• progression-free survival (PFS),
• site-specific activity such as locoregional control
 PHASE III - THERAPEUTIC CONFIRMATION

• Randomised, double blind, multi-centric controlled trials; 250- 1000+

• Cross over design
• Patients
• Objectives:
• Efficacy on a substantial scale; safety;
• Comparison with existing drugs.
• Drug interactions
• Guidelines for use of drug
Phase III
• Are randomized comparisons between a new treatment regimen that
has already shown promise in phase I/II trials and the current best
standard of care (i.e., the control).
• Randomization balances the distribution of prognostic factors
between treatment arms and ensures that treatment is assigned
independent of any bias
• Designed to compare a new treatment with the current standard
treatment, also compare two or three different regimens with each
other, as well as with standard treatment.
Phase III
• End point of a phase III trial
• Overall survival (time to death from any cause)
• Disease-free survival (DFS)
• locoregional control
• adverse event profiles
 NEW DRUG APPLICATION
• If phase 3 results meet expectations, application is made for
permission to market the new agent.
• Marketing approval requires submission of a New Drug Application
(NDA) to the DRA.
• The application contains, full reports of all preclinical and clinical data
pertaining to the drug under review, package inserts.
Phase IV
• Also known as a postmarketing surveillance trials
• Involve the safety surveillance of a drug after it receives regulatory
approval for standard use.
• Designed to detect any rare or long-term adverse effects over a much
larger patient population and longer time period.
 UNIQUE FEATURE OF CLINICAL TRIALS IN
RADIATION ONCOLOGY
• Involve the introduction of new technologies
• use of stereotactic body radiation for a new indication
• novel combination of radiation therapy with a systemic agent.
• End point for radiation trials -
• Progression free survival(PFS) - difficult to objectively assess.
• Imaging end points (such as fluorodeoxyglucose [FDG] uptake)
 UNIQUE FEATURE OF CLINICAL TRIALS IN
RADIATION ONCOLOGY
• End points depend on multiple factors
• size of the target
• proximity of tumor to sensitive normal tissues,
• accuracy of target volume definition,
• degree of patient immobilization,
• dose of radiation
• fractionation scheme.
• quality-assurance measures
 CLINICAL TRIAL – BASIC CONSIDERATION
• Objective of the Trial –
• Medical questions that need to be answered should be clearly
formulated.
• A trial can have more than one objective.
 CLINICAL TRIAL – BASIC CONSIDERATION
• Patient Population Definition and Stratification
• Population defined in terms disease characteristics - prognosis, stage tumour
pathology or marker
• Must be unambiguously defined.
• Use of stratified randomization approach to ensure equal representation of
characteristics among treatment arms.
CLINICAL TRIAL – BASIC CONSIDERATION
• Randomization
• Done to render treatment groups similar with respect to factors that
can influence outcomes.
• In phase II trials, randomization has been used in
• selection designs to help decide which of several potential candidate
treatments to take forward to further definitive testing.
• provide evidence that a test treatment is indeed promising
• In phase III, randomization is critical for definitive unbiased
evaluation
CLINICAL TRIAL – BASIC CONSIDERATION
• Factors affecting randomization
• Breach of the random assignment process
• a large number of patient withdrawals
• differential follow-up
• Bias in assessment of outcomes
• Treatment assignment blinding is not feasible for radiotherapy
CLINICAL TRIAL – BASIC CONSIDERATION
• End points
• unambiguously defined,
• be assessable and reproducible
• reflect the action of the intervention.
• single primary end point, there may be numerous secondary end points.
CLINICAL TRIAL – BASIC CONSIDERATION
• Sample Size
• Depends on endpoint
• Patients with-drawing from treatment (dropout),
• Switching from the assigned treatment to the other group (crossover)
• Deviating from protocol treatment (noncompliance).
CLINICAL TRIAL – BASIC CONSIDERATION
• BLINDING - an experimental condition in which various groups of the individuals involved
with the trial are withheld from the knowledge of the treatments assigned to
patients and corresponding relevant information.
• Purpose is to eliminate bias in subjective judgment due to knowledge of the treatment.
• Blinding in clinical trials can be classified into four types:
• An open-label study - in which no blinding is employed.
• A single-blind trial - in which only the patient is unaware of his or her treatment
assignment.
• A double-blind trial - in which neither the patients nor the investigator (study centre) are
aware of patient’s treatment assignment. The blindness also applies to concealment of
the overall results of the trial.
• A triple-blind study with respect to blindness can provide the highest degree for the
validity of a controlled clinical trial.
CLINICAL TRIAL – BASIC CONSIDERATION
• Interim Analysis and Stopping Rules
• used in all phases of clinical trials.
• provide for early decision making in a trial regarding continuation, disclosure
of findings, or modification of the trial while preserving integrity of the study
• Phase I trials stopping rules - termination of enrollment based on observed
cumulative adverse event rates at a given time
• Phase II trials stopping rules, usually restricted to futility stopping, or
discontinuation when results do not appear promising.
• Phase III trials use group sequential methods.
• Primary hypothesis is evaluated at predefined increments of the total
information needed for definitive analysis.
CLINICAL TRIAL – BASIC CONSIDERATION
• Definitive Analysis
• When a trial reaches maturity either as planned or earlier as a result
of the monitoring plan, then definitive analysis takes place.
• Prior to this, it not recommended to disclose any results from the
trial
 HIGH-QUALITY CANCER CLINICAL TRIALS
• Involves the cooperation of -
• cancer patients and their families,
• physicians (who accrue the patients),
• Operating environment (academic institution or practice),
• The research team (who runs the trial on a day-to-day basis),
• Sponsors (who oversee and fund the trial),
• Independent monitors (to ensure the correct performance of the research
team),
• Government regulatory agencies
• Clinical psychologists
OVERVIEW OF ETHICAL CONSIDERATIONS
• Medical ethics are based on –
• the principles of autonomy (the patient’s right to refuse or choose
treatment),
• beneficence (a practitioner should act in the best interest of the
patient),
• non-maleficence (first, do no harm),
• justice (fairness and equality),
• dignity, and honesty.
• Documents seeking to address these issues include the Nuremberg
Code, the declaration of Helsinki, and the Belmont Report.
 CLINICAL TRIAL DESIGN

• Parallel Group Design: is a complete randomized design in which

each patient receives one and only one treatment in a random
fashion.
TEST

RANDOMIZATION
RUN IN
PATIENTS CONTROL A

CONTROL B
 CLINICAL TRIAL DESIGN

• RUN IN PERIOD
• Before patients enter a clinical trial, a run-in (or lead-in) period of placebo, no
active treatment, dietary control, or active maintenance therapy is usually employed
prior to randomization.
• Advantages:
• It acts as a washout period to remove effects of previous therapy.
• It can be used to obtain baseline data and to evaluate if patient fulfils study entry
criteria.
• It can be used as a training period for patients, investigators, and their staff.
• It helps in identifying placebo responders.
• It provides useful information regarding patient compliance.
• It can be used to estimate and compare the magnitude of possible placebo effects
between groups
 CLINICAL TRIAL DESIGN

• Crossover Design:
• Each subject is randomised to a sequence of two or more
treatments, and hence acts as his own control for treatment
comparisons.
PERIOD
I II
TEST CONTROL
SEQUENCE A

RANDOMIZATION

WASHOUT
PATIENTS

SEQUENCE B CONTROL TEST

STANDARD TWO-SEQUENCE, TWO-PERIOD CROSSOVER DESIGN

 CLINICAL TRIAL DESIGN

• Factorial Design:
• Two or more treatments are evaluated simultaneously through
the use of varying combinations of the treatments.
 CONDUCT, AND REPORTING OF CLINICAL
TRIALS
• Protocol Document and Study Conduct
• The goal of a clinical trial is to change clinical practice.
• The clinical trial protocol document must contain –
• The title, investigator and sponsor names
• Phase (I, II, or III), protocol synopsis, background knowledge, study design and
schema,
• Objectives, methodology, subject selection criteria, registration procedures,
• Treatment plan, dosing modifications, adverse events reporting,
• Data and safety monitoring plan, study calendar, outcome measures, data
reporting, statistical considerations, and the informed consent
• For Conduct of study –
• The investigators must know the current state of knowledge on the studied
disease
• Clearly describe the eligibility criteria of the studied population
• Understand the number of patients who will be eligible in their
institution/cooperative group
• Choose simple and achievable end points
• Establish statistical assumptions based on thorough review of pre-existing
data
• Collaborate with a biostatistician to decide on study design, sample size, and
power.
• Data and Safety Monitoring Committees(DSMC)-
• Take decision to-
• Alter a clinical trial in progress,
• Including discontinuation of treatment
• To release findings early
• Trial Reporting
• Once a study is completed and the data are fully analyzed, its results should
be reported promptly.
• The Consolidated Standards of Reporting Trials (CONSORT) statement is used
worldwide to improve the quality of reporting of randomized controlled trials.
 CONSORT FLOW DIAGRAM
Assessment for eligibility

Enrollment
Excluded

Randomization

Allocation TEST CONTROL

Allocated to Intervention Allocated to Intervention

Did not receive Did not receive

Received Intervention Received Intervention

Follow-Up Lost to Follow up Lost to Follow up

Followed Up Followed Up

NotAnalyzed NotAnalyzed
Analysis
Analyzed Analyzed

CONSORT - Consolidated Standards of ReportingTrials

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 RECENT APPROACHES TO CLINICAL
TRIAL DESIGN
• An Alternative Phase I Design for Radiation Oncology Trials
• Phase I trials in radiation therapy present a unique challenge
• Toxicities may occur long after treatment and need to be incorporated into
dose evaluation.
• Traditional designs do not accommodate this
• Time-to-event continual reassessment method (TITE-CRM), was developed
that incorporates the time-to-event (i.e., time-to-toxicity) information for
each patient
• TITE-CRM method was associated with slightly more toxicities, particularly in
situations where events tend to occur near the end of the observation period,
because escalation to the next dose may have already occurred before
toxicities were observed.
 RECENT APPROACHES TO CLINICAL
TRIAL DESIGN
• Using Biomarkers as Inclusion Criteria
• response of tumours to targeted agents highly depends on their
molecular subtype.
• Consequently, trials increasingly screen for molecular characteristics
of tumours to use as eligibility criteria or, at a minimum, stratification
factors.
• Recent examples are the Biomarker-integrated Approaches of
Targeted Therapy for Lung Cancer Elimination (BATTLE) trial in lung
cancer and the I-SPY trials in breast cancer.
 MOVING BEYOND CLINICAL TRIALS
• Meta-Analysis
• Refers to process whereby data from several independent studies are
combined to form a quantitative summary estimate of a given effect.
• Considered by some to be a level I evidence source along with large
randomized clinical trials.
• Performing a systematic analysis of data from all identified randomized
trials can define a modest yet real advantage associated with a new
therapeutic approach.
• The choice of trials to be included is critical, because analysing trials
with disparate patient populations or treatment methods may lead to
erroneous conclusions.
• Can be influential in guiding treatment practice.
THANK YOU