Drug Development :

Basic Overview of Clinical Trials:

Phase I-III

Patricia Mucci LoRusso, D.O.

Associate Center Director – Innovative Medicine
Yale Cancer Center
 Tr ia ls
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ll i n C T ri als
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en t s i n C l
P a ti nr o l l
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f all C e ri c p re s
o A m e rr e
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% o fA e n are
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Aggregate Patient Recruitment Success
Rates

How do patients learn about

trials? – CISCRP

Tufts CSDD; N=3,534 Phase II-IV protocols

*Cutting Edge Information, “Clinical Operations Benchmarking Per-Patient Costs, Staffing and Adaptive Design” 2011
Non-performing Sites By Therapeutic Area

“Addressing Ever-Rising Cost in Conducting Clinical Trials”

Covance Inc. 2015
One Large Scale Oncology Trial

“Addressing Ever-Rising Cost in Conducting Clinical Trials”

Covance Inc. 2015
 Non-Performing Sites

• Average $50k start-up cost

• Result in budget overrun
• Many never enroll a single patient or very few
• Selection of sites often carried out in a non-
scientific, non-systematic way
• Causes delay, impacting trial schedule
• $334.70 million wasted on non-performing
oncology sites from 2006-2011

“Addressing Ever-Rising Cost in Conducting Clinical Trials”

Covance Inc. 2015
 Potential Accrual Barriers – Patient Level
• Awareness of trials as an option
• Understanding of what trial participation involves
• Concerns around side effects
• Education about particular trial phase
• Education about particular treatment
• Fear of distrust (guinea pig) instead of trust in physician
recommendations
• History of discrimination in medical research
• Inconvenience of trial logistics: travel, times, number of visits
• Financial burden
How do patients learn about trials? – CISCRP
 Barriers to Enrollment – Physician Factors
• Concerns about potential toxicity from study treatment
• Concerns about comorbid conditions of patients
• Lack of awareness of accessible clinical trials
• Lack of access to clinical trials
• Physicians’ own perceptions about the relevance of the
questions being addressed in the available trials
• Lack of time in busy practices to discuss trial options
 Potential Accrual Barriers – Provider Level

• Payment metrics at respective practice

• Time & resources required to discussing trials
• Fear of “losing” patients if refer to clinical trials
• Concerns around trial suitability for patient (eg tolerability, benefit)
• Belief patient should not be offered trial (not adherent, competent)
• Comfort with, and style of, communicating trial to patients
 Barriers to Enrollment

• Lack of encouragement or support from the attending

physician
– Unaware of appropriate open trials
– Lack time to discuss options at length
– Concerned about lack of control over their patient
• Unrealistic, inconvenient protocol requirements
• Unrealistically restrictive inclusion/exclusion criteria
– The most motivated patients are most likely to be excluded
– Rejected patients often don’t try again
 Barriers to Enrollment (cont.)
• Politics
– Rivalry between physicians and/or hospital administrators
• Bad publicity
– Trials conducted unethically garner the most press
• Physician or hospital concerns about potential liability
• Insurance or HMO policies that may preclude
reimbursement for care or make it difficult
• HIPAA restrictions
• Standardized order sets for “quality”
 Logistics Factors
• Physicians – lack of support and infrastructure (trial
nurses, study coordinators, pharmacy capability, etc) to
enable enrollment of patients into trials
• Reimbursement of costs incurred by patients during
participation in clinical trials (e.g. parking)
• Patient – lack of social support to attend doctor visits
(e.g. for study treatment, management of treatment-
related adverse events)
• Language barrier
 Trial Factors
• Dissemination of up-to-date knowledge of available and
ongoing trials and how to access them
• Paucity of trials for specific patient populations e.g.
hepatic/renal dysfunction, elderly
• Changing landscape in clinical trial designs e.g. histologic
and/or molecular selection including rare subsets
• Need for innovative and attractive clinical trials that
efficiently evaluate novel agents
• Burden of research investigations and visits in clinical
trials
 Potential Accrual Barriers – Site Level

• Staffing (research nursing & support staff)

• Redundant review processes
• Slow trial activation
• CRO relationships & issues
• Lack of standard processes for patient screening
• Lack of effective clinical trials tools
 Potential Accrual Barriers – Systems Levels

• Overly optimistic accrual goals and/or limited accrual

feasibility assessment prior to activation
• Inadequate recruitment planning during trial development
process
• Limited funding & incentives for site & provider involvement
(to conduct & offer trials)
• Trial availability & eligibility for incident patients (eg exclusion
for comorbidities, prior # treatments)

Massett, et al., Clin Can Res, November 2016

 Clinical Trials

• Clinical trial: a prospectively planned

experiment for the purpose of evaluating
potentially beneficial therapies or treatments
• In general, these studies are conducted
under as many controlled conditions as
possible so that they provide definitive
answers to pre-determined, well-defined
questions
Primary vs. Secondary Questions
• Primary
– most important (i.e., central question)
– ideally, only one
– stated in advance
– basis for design / sample size calculations
• Secondary
– related to primary
– also stated in advance
– limited number but usually more than one
 Why Clinical Trials?
Most definitive method to ultimately
determine treatment effectiveness

– Other designs more potential biases

– One cannot determine in uncontrolled
setting whether intervention has made
a difference in outcome
– Correlation versus causation
 Why Clinical Trials?

• Help determine incidence of side

effects and complications

• Theory not always best path

– May not actually prove itself in reality
– May not be tolerable/ feasible solution
 Elements of Clinical Protocols
• Objectives – Primary and Secondary
• Biostatistics
• Patient selection criteria – Inclusion/Exclusion
• Therapeutic Intervention
• Dose and Schedule and Mechanism/Route of Delivery
• Clinical Work-up and Follow-up Assessment
• Toxicity
• Toxicity criteria
• Dose modifications
• Efficacy
• Clinical, pharmacodynamic (PD) and QOL
• Analysis and interpretation
• Primary & secondary endpoints
• Correlative studies
 Questions to be Answered in Clinical
Trials
•Why?
•Who?
•What?
•Which?
•Where?
•When?
•How (bad)?
•So what?
 Why: Define Trial Objectives
• Why are you doing this study?
• “The primary objective of this trial is …”
• Limit number of objectives
• Too many will limit trial success
• Well planned & thought out objectives
• Biostatistics important here
• Critical outcome for study a “go/no go” decisions?
• Define and use secondary endpoints to generate hypotheses to be
explored in future research
• Remember laboratory correlative objectives
• “translational research”
• Make sure assay and tissue available
• Confirm reproducibility and relevance
• Design must take this into account when answering this question!
 Who: Patient Selection
• Who should enter the trial?
• One of the most critical factors affecting study outcome
• Each selection criterion should be based on a sound scientific,
medical, ethical rationale
• Do not copy/paste from other trials!
• Inclusion/exclusion should be study directed
• Disease type
• Prior treatment
• Age, sex, organ function and other variables
• Measurability and disease status

Proper patient selection is key for successful completion and

scientific impact of your study!
 What: Trial Intervention
• What treatment?
• What dose and schedule?
• Which dose or schedule variations are planned?
• How long may the treatment last?
• What are specific steps in drug administration?
• What should be done to prepare, treat, and monitor the patient
prior/during/after treatment?
• Will the same treatment be given to all patients?
• If not, what are the differing procedures?
• What are the methods to assess compliance with the
procedures defined in your protocol?
Which: Assessment of Critical Endpoints
WHICH:
• Methodology is used to select patients (Performance
status? Pain score? NYHA?...)
• Standard will be used to assess response?
• Instrument for evaluation of safety and toxicity
• Methodology to be applied for the statistical,
correlative and translational endpoints?
Where: Tumor and Response Assessment
• Where are primary tumor lesions to be measured?
• What happened to it during treatment?
• Location, size, density
• Criteria for response: RECIST vs. WHO
• Define deviations from standard methodology
• Pre-baseline assessment of progression required?
• Target vs. non-target lesions
• Other clinical or correlative parameters of effect being studied
adequately?
• TTP, TTF, OS, duration of response, etc.
• Growth modulatory rate
• Immune response
• Target modulation in tumor tissue or surrogate
• Functional imaging
 When: Timing of Assessment
• When will assessments of primary, secondary and
translational endpoints be performed?
• Is the timing of assessments compatible with the
chosen endpoints?
• Will dose delays or modifications affect the schedule
of reassessment?
• Will there be a sufficient number of patients remaining
on study to obtain adequate information?
• Is the chosen timing compatible with the routines of
physicians, nursing staff, hospital and patient?
 How (bad): Safety and Toxicity
• To what degree does treatment interfere with patient
well-being?
• How assessed (CTC? QoL? Self-made instrument?)
• What modifications are incorporated to avoid or
minimize the risk or severity of toxicity?
• Dose reduction
• Dose delay
• Dose omission
• Supportive care (prophylaxis, intervention, secondary
prevention)
• Discontinuation of individual treatment?
• Termination from the study (specify criteria!)
 So What: Analysis and Interpretation
• Has study design been followed, is the trial “mature”?
• Evaluate the compliance of all involved parties
• So what do the results and observations mean?
• Primary endpoint reflects the hypothesis tested
• Secondary endpoints reflect hypotheses generated
• Have the appropriate statistical tools been used?
• Beware of sporadic “significant” results that result from
multiple, unplanned comparisons
• Beware of retrospective subgroup analyses

Given the results, how should we move forward (go/no go;

generate confirmatory evidence in laboratory models;
additional clinical trials…)?
Definitions
 Definitions

• Single Blind Study: A clinical trial where

the participant does not know the identity
of the treatment received

• Double Blind Study: A clinical trial in

which neither the patient nor the treating
investigators know the identity of the
treatment being administered.
 Definitions
• Placebo:
– Used as a control treatment

1. An inert substance made up to physically

resemble a treatment being investigated
2. Best standard of care if “placebo” unethical
3. “Sham control”

4. Used in Randomized trials

 Definitions
• Adverse event:
– An incident in which harm resulted to a person
receiving health care.
– Examples: Death, irreversible damage to liver,
nausea, drop in white cells or platelets
– Not always easy to specify in advance because
many variables will be measured
– May be known adverse effects from earlier trials
or preclinical toxicology studies
• Animals and man different – can’t always predefine
– Not necessarily linked to assigned treatment
• Important to decipher if drug effect
 Adverse Events (Aes)

• Challenges
– Long term follow-up versus early benefit
– Rare AEs may be seen only with very large numbers
of exposed patients and/or long term follow-up
• Example – COX II inhibitors
– Vioxx & Celebrex
– Immediate pain reduction versus longer term
increase in cardiovascular risk
 Characterization of Trials
Phase Single Center Multi Center
Randomized Non-Rand. Randomized Non-Rand.

I Never Yes Never Sometimes

II Rare Yes Yes Sometimes

III Yes Use of Yes Use of

Historical Historical
Controls Controls

Carrying out a multi-center randomized clinical trial is the most difficult

way to generate scientific information.
 Phase I Trial
• Primary Objective : Determine an acceptable range
of dose(s) & schedule(s) for a new drug
– Determine toxicities (dose-limiting and others)
• Secondary Objectives: Pharmacokinetics,
Pharmacodynamics and Anti-tumor Activity
• Usually seeking maximum tolerated dose or target
dose based on pre-clinical exposure
– Maximum biological dose

• Participants have often failed other treatments

• Important to have adequate performance status &
“normal” organ function (except organ dysfxn trials)
– Not an alternative to Hospice
Definitions of Key Concepts in Phase 1 Trials

• Pharmacokinetics (PK):
– “what the body does to the drug”
– ADME: absorption, distribution, metabolism and
excretion
– PK parameters: Cmax, AUC (drug exposure), t1/2,
Clearance, etc.
• Pharmacodynamics (PD):
– “what the drug does to the body”
– e.g. nadir counts, non-hematologic toxicity, molecular
correlates, imaging endpoints
 Phase I Design Strategy

• Designs often based on tradition

• Typically do some sort of dose escalation to
reach targeted endpoint (MTD, OBD, MFD)
• Has been shown to be safe and reasonably
effective
• Dose escalation based on mathematical
model: Fibonacci, 2-fold escalation,
Continuous Reassessment Method, etc.
 Examples of Study Schemes

A. Fibonacci
B. “Standard”
C. “1 Up, 1 Down”
D. “2 Up, 1 Down”
E. “Extended Standard”
F. Baysian
G. Continuous Reassessment Method
H. Currently, significant alteration of previous trial
designs – Fit for Purpose
 Typical Scheme
1. Enter 3 patients at a given dose
2. If no toxicity, go to next dosage and repeat
Step 1
3. a. If 1 patient has serious toxicity, add 3 more
patients at that does (go to Step 4)
b. If 1/6 have serious toxicity, consider MTD
4. a. If 2 or more of 6 patients have toxicity,
drop down 1 dose to confirm safety
b. If 1 of 6 has toxicity, increase dose and go
back to step 1
 Types of Phase 1 Trials
• Multiple types of Phase 1 Trials
– Dose finding
– Food effect study
– QTc prolongation study
– Bioequivalence study
– Approved or investigational agent with pharmacokinetic
focus (adding of CYP inhibitor)
• Typically considered drug-drug interaction study
– Investigational agent + investigational agent
– Investigational agent + approved agent(s)
– Approved agent + approved agent(s)
– Approved or investigational agent with
pharmacodynamic focus (e.g. evaluation using
functional imaging)
– Approved or investigational agent with radiotherapy
 Phase II Trials

• Objective: To determine if new drug has

any beneficial activity and thus worthy of
further testing / investment of resources.
• Doses and schedules may not be optimum
• Begin to focus on population for whom this
drug will likely show favorable effect
 Phase II Trials
Goal
– Screen for therapeutic activity
– Further evaluate toxicity
– Test using MTD or defined Dose(s) &
Schedule(s) from Phase I (RP2D)
– Make go/no-go decisions for Phase III trials
– Perform translational work
Might also randomize patients into multiple
arms each with a different dose and/or
schedule
– can then get a dose response curve
 Phase II Design

• Design(s)
– No control (is this wise?)
– Two-stage (double sampling)
– Goal is to reject ineffective drugs ASAP

Decision I:Drug unlikely to be effective in  x% of patients

Decision II: Drug could be effective in  x% of patients

• Other two-stage designs based on determining p1-p0 > x%

where p0 is the standard care combination
 Phase III Trial
• Objective : To compare experimental or
new therapies with standard therapy or
competitive therapies
– Often large & expensive studies
– Typically required by FDA for drug approval

If drug approved, often followed by Phase IV

trials to follow-up on long-range adverse
events – concern is safety
 Phase III Trial Designs
• The foundation for the design of controlled experiments
established for agricultural experiments

• The need for control groups in clinical studies

recognized, but not widely accepted until 1950s

• No comparison groups needed when results dramatic:

– Vismodegib in Advanced Basal Cell Carcinoma

• Use of proper control group necessary due to:

– Natural history of most diseases
– Variability of a patient's response to intervention
 Phase III Design
• Comparative Studies
• Experimental Group vs. Control Group
• Establishing a Control
1. Historical
2. Concurrent
3. Randomized
• Randomized Control Trial is gold standard
– Eliminates several sources of bias
 Purpose of Control Group

• To allow discrimination of patient

outcomes caused by test treatment vs
those caused by other factors
– Natural progression of disease
– Observer/patient expectations
– Other treatment
• Fair comparisons
– Necessary to be informative
 Significance of Control Group

• Inference drawn from the trial

• Ethical acceptability of the trial
• Degree to which bias is minimized
• Type of subjects
• Kind of endpoints that can be studied
• Credibility of the results
• Acceptability of the results by regulatory authorities
• Other features of the trial, its conduct, and
interpretation
 Use of Placebo Control
• The “placebo effect” is well documented
• Could be
– No treatment + placebo
– Standard care + placebo
• Matched placebos necessary so patients &
investigators cannot decode the treatment assignment
• eg. Vitamin C trial for common cold
– Placebo was used, but was distinguishable
– Many on placebo dropped out of study – not
blinded
– Those who knew they were on vitamin C reported
fewer cold symptoms and duration than those on
vitamin who didn't know
 Historical Control Study
• A new treatment used in a series of subjects

• Outcome compared with previous series of comparable

subjects

• Non-randomized

• Rapid, inexpensive, good for initial testing of new

treatments

• Vulnerable to biases
Different underlying populations
Criteria for selecting patients
Patient care
Diagnostic or evaluating criteria
 Randomized Control
Clinical Trial

• Patients assigned at random to either

treatment(s) or control

• Considered to be “Gold Standard”

 Disadvantages of Randomized Control
Clinical Trial
1. Generalizable Results?
– Subjects may not represent general patient
population – volunteer effect

2. Recruitment
– Twice as many new patients

3. Acceptability of Randomization Process

– Some physicians will refuse
– Some patients will refuse

4. Administrative Complexity
 Comparing Treatments
• Fundamental principle
• Groups must be alike in all important aspects and only differ in the
treatment each group receives
• In practical terms, “comparable treatment groups” means
“alike on the average”

• Randomization
• Each patient has the same chance of receiving any of the
treatments under study
• Allocation of treatments to participants is carried out using a
chance mechanism so that neither the patient nor the physician
know in advance which therapy will be assigned

• Blinding
• Avoidance of psychological influence
• Fair evaluation of outcomes
 Randomized Phase III Experimental Designs

Assume:
• Patients enrolled in trial have satisfied eligibility
criteria and have given consent
• Balanced randomization: each treatment group will
be assigned an equal number of patients

Issue
• Different experimental designs can be used to
answer different therapeutic questions
Commonly Used Phase III Designs
• Parallel
• Withdrawal
• Group/Cluster
• Randomized Consent
• Cross Over
• Factorial
• Large Simple
• Equivalence/Non-inferiority
• Sequential
 Conclusions
1) Clinical Trials are a necessary
component of cancer drug development
2) There are discrete developmental phases
of clinical drug development, often with
some endpoint overlap (1o or 2o):
1) Phase I Trials, although many different
types, are typically answering questions for
one of the first times in man
2) Phase II Trials are focused on efficacy
3) Phase III Trials help determine benefit over
Stand of Care treatment
We must work together in the fight
against Cancer – please encourage
patients and caregivers to consider
treatment on a clinical trial