Clinical Trial Protocol &

Amendments

William Petros, PharmD, FCCP

Professor, Schools of Pharmacy & Medicine
Associate Director for Anticancer Drug Development
Mary Babb Randolph Cancer Center
West Virginia University
 Outline

I. Rationale for Clinical Trials

II. Preclinical Testing
III. Types of Clinical Trials
IV. Elements of the Protocol
 Why do we need clinical trials?
• Clinical trials separate therapies which are
true advances from false leads and clinical
impressions. Importantly, they also identify
risks of therapy.
 Brief History Leading to Clinical Trials

• 1937 Liquid formulation of sulfa drug sold with diethylene

glycol, killing > 100
• 1938 (US FDC Act) mandated pre-market safety evaluation
• 1961 Case reports of thalidomide (approved in Europe)
causing server birth defects and deaths
• 1962 Legislation mandates FDA approval contingent on
“substantial evidence” of safety (first in animals and then
humans) in addition to efficacy
 Clinical Trials
• Prospective studies comparing the effect and
value of an intervention in humans (or
sometimes animals)
– Can involve drugs, devices, procedures, etc.
• Informed consent required
• In some settings, these are considered the
standard of care e.g. many pediatric
malignancies
What Is the focus of a clinical drug trial?
Examples:
• Effectiveness of intervention to treat a
disease
• Safety of a new drug
• Defining dose administration
• Testing drug formulation
• Exploring combination therapies
• Evaluating effect of therapies on quality of
life
 Rationale for Clinical Trials
Need….
• “If you don’t want to practice medicine 10 years
from now the same way we do it today then
clinical research must be a priority.” (MH Jan
2013)
Approach….
• Animal studies are of limited value in
determining the full spectrum of toxicities and
predicting effectiveness of treatments in humans
 Outline

I. Rationale for Clinical Trials

II. Preclinical Testing
III. Types of Clinical Trials
IV. Elements of the Protocol
 Contents of a full Investigational
New Drug Application (IND)
1. Form FDA 1571
2. Table of Contents
3. Introductory statement
4. General Investigational plan
5. Investigator’s brochure
6. Protocol
a. Study protocol
b. Investigator data or completed Form FDA 1572
c. Facilities data or completed Form FDA 1572
d. Institutional Review Board data or completed Form FDA
1572
7. Chemistry, manufacturing, and control data
8. Pharmacology and toxicology data
9. Previous human experience
 Overview of Pre-Clinical Anti-Cancer
Drug Development

Cell Culture
Animal Tumor Models
Human Xenografts

Pharmaceutics & Tox

Human Clinical Trials

 Pre-Human Testing

• Mix drug with cancerous

and normal cells grown in
lab
 Pre-Human Testing

• Evaluation of drug in
animals
– Effectiveness
– Toxicity
 Outline

I. Rationale for Clinical Trials

II. Preclinical Testing
III. Types of Clinical Trials
IV. Elements of the Protocol
 Types of Clinical Trials
Therapeutic:
• Treatment
– Test new approaches to treat a disease
• Prevention
– What approaches can prevent disease
Non-therapeutic:
• Early-detection/screening
– What are new ways to find hidden disease
• Diagnostic/Prognostic/Epidemiologic
– How can new tests or procedures ID disease
http://www.fda.gov/cder/handbook/develop.htm

Post-marketing
studies
 Overview of Clinical Drug Development

Pre-clinical
Phase I Safety/Early Activity/Pcol/Dosing

Phase II Activity/Safety/Dosing

Phase 0 Phase III Tx Improvement

MOA
FDA Approval
 Phase I Trials
• Goals:
– Evaluate the nature of toxicities
– Determine the “maximally tolerated dose” or
“optimal biologic dose” or alternative target
– Identify a feasible schedule of administration
– Investigate the way in which the drug
distributes and is eliminated from the body
– Observe any anti-tumor effects
– Investigate surrogate response markers
 Common Issues Addressed by Clinical Pharmacology
Studies in the Drug Development Process
 Phase I
• Bioactive concentrations, in vitro
vs. vivo
• Human metabolism & renal
influence
• Intra-patient and inter-patient
variability
• Weight/BSA associations
• Bioavailability
• Linearity
• Pharmacodynamic surrogate
• Pharmacogenomics
 Phase I Trials (continued)
• Patients:
– Normal volunteer (non cancer)
– Relapsed following typical anti-cancer
therapies
– Newly diagnosed cancers with no effective
therapy
– May be required to “overexpress” the target
• Design:
– Single-Drug
– Combination (new and old drug)
 Phase I Trials (continued)
• Single anti-cancer drug design:
– E.g. Treat 3 patients at a very low dose, if
acceptable toxicity, then double dose to next
group of patients
– Intra-patient does escalations atypical
• Multiple anti-cancer drug design:
– Same as above but escalate doses for each agent
individually
 Typical Dose-Limiting Toxicity Criteria
for an Anti-Cancer Drug

• ANC < 500 for > 5-7 days

• ANC < 1000 + fever of 38C or above
• PLT < 10K or 25K
• Grade 3-5 non-hematologic toxicity
• Inability to retreat within 2 weeks of schedule
secondary to toxicity
 Phase I Endpoints for
Non-Traditional Anti-Cancer Drugs*

• Dose-limiting toxicity (DLT)

• Target plasma concentration
• Saturation of drug clearance (monoclonals)
• Elucidation of a pharmacologic (surrogate)
effect in either normal or malignant cells

*Dose-response could be non-monotonic

 Phase I Trials (continued)
• Information needed for next phase:
– Appropriate dose and schedule
– Refined toxicity monitoring parameters
– Suggestions for activity in specific malignancies
– Identification of surrogate markers for activity
 Phase II Trials
• Goals:
– Determine the effectiveness in specific types of
cancer and compare this to literature on other
drugs
– Further refine the dose & schedule of
administration
– Evaluate the nature of toxicities when given for
a longer term
– Evaluate associations of surrogate markers with
response
 Phase II Trials (continued)
• Patients:
– Non-responders or relapsed following a typical
therapy
– Initial therapy for some cancers that have
spread beyond the initial site
– May be required to “overexpress” the target
• Design:
– 30-60 patient studies with therapy given over
several months to evaluate anti-cancer
response
 Phase II Trials (continued)
• Structure
– Single arm, historic control
– Targeted biologic endpoint
– Single arm, intra-patient control
– Randomized vs. other anti-cancer agents
– Randomized discontinuation
– Cross over, double-blind
 Common Issues Addressed by Clinical Pharmacology
Studies in the Drug Development Process

 Phase II
• Dose optimization
• Schedule optimization
• Patient compliance
• Pharmacometrics
• Pharmacogenomics
• Interactions
– (drugs, disease, excipients, herbals, food, etc.)
Accelerated Approval May Occur After Phase II

Schwartsmann, et al. JCO, 2002

 Phase III Trials (continued)
• Patients:
– Wider eligibility criteria
– Initial diagnosis of cancer or situations where initial
chemotherapy is indicated
– May be required to “overexpress” the target
• Design:
– Large numbers of patients randomized to receive
investigational therapy or placebo vs. the standard
– Non-inferiority vs. equivalency vs. superiority
 Phase III Trials (continued)
• Typical sites:
– Large, academic cancer centers
– Some smaller cancer centers
– Some larger private practice groups
– Cooperative groups

• File NDA once successfully completed

 Post-Approval Studies (Phase IV)
 Drug-drug  Strategies for
interactions minimization of
 Drug-food interactions adverse effects
 Drug-herbal  Strategies for dose-
interactions individualization
 Pharmacoeconomic  Optimization of
 Expanded surrogate lab tests
safety/efficacy  Special populations
 Additional indications  New formulations
 Outline

I. Rationale for Clinical Trials

II. Preclinical Testing
III. Types of Clinical Trials
IV. Elements of the Protocol
 Elements of the Protocol
• Title page • Background
– Title
– Key studies
– Investigators/team
– Number, version, date
– Not an exhaustive review
– IND # (if applicable) • Rationale/Justification
– Institutions of conduct – Objectives
– Sponsor
– Overall design
• Schema*
– Ancillary studies
– Overview of treatment regimen
• Table of Contents – Unique methods
• Objectives – Population
– Clearly stated – Doses
– Primary • Eligibility Criteria
– Secondary
– Tertiary (exploratory)
Eligibility Criteria/Study Population
• Clear and verifiable eligibility criteria that are
not too narrow, yet address the objective(s)
without inflicting too much heterogeneity
– Inclusions
• e.g. diagnosis, extent (spread) of disease, measurability
of disease, age, anticipated survival, tumor genetics,
“adequate” organ function, informed consent, etc.
– Exclusions
• e.g. concomitant disease(s), prior treatments,
pregnancy, poor “performance status” etc.
 Elements of the Protocol
• Title page • Background
– Title – Key studies
– Investigators/team – Not an exhaustive review
– Number, version, date • Rationale/Justification
– IND # (if applicable) – Objectives
– Institutions of conduct – Overall design
– Sponsor
– Ancillary studies
• Schema* – Unique methods
– Overview of treatment regimen – Population
• Table of Contents – Doses
• Objectives • Eligibility Criteria
– Clearly stated
• Treatment plan/Study design
– Primary
– Administration schedule/doses
– Secondary
– Schedule/dose modifications
– Tertiary (exploratory)
– Duration of therapy
 Typical Study Design Features
• Treatment sequences
– e.g. single, parallel, crossover, withdraw, survival
• Blinding/masking
– e.g. open label, single blind, double blind,
double dummy
• Control
– e.g. hx, no tx, dose response, active, placebo
• Methods of assigning treatment
– e.g. randomization +/- stratification
 Elements of the Protocol (continued)
• Supportive care • Adverse events
• Pharmaceutical info – List (labs vs. symptoms)
– Procurement/supply – Reporting requirements
– Preparation – Data & safety monitoring
– Storage & stability plan
– Administration route
– Adverse effects
– Drug interactions
• On study procedures
– Registration
– Randomization
– Stratification factors
NCI’s Common Terminology Criteria for
Adverse Events (CTCAE)
 Adverse Events
• Adverse Event
– Any untoward medical occurrence associated with the use of a drug
in humans, whether or not considered drug related
– Labeled an Adverse Reaction if thought to be caused by the drug
– Unexpected Adverse Event if not listed in the investigators’ brochure
or at the specificity or severity observed
• Serious Adverse Event
– Death, life-threatening, hospitalization (or prolongation), persistent
or significant disability, congenital/birth defect, medically important
that jeopardizes patient and need intervention to prevent previous
issues (e.g. bronchospasm requiring intensive o/p treatment)
– Severe not necessarily serious (e.g. gr 3 headache)
• Life Threatening Event
– Places patient at immediate risk of death
39
 Data & Safety Monitoring Plan
• Required in all NIH supported clinical trials and typical in
many pharma phase III studies
• Ensures patient safety, data validity and appropriate
termination of studies if undue risks or if the trial cannot
be completed successfully
• Required Elements
– Delineation of oversight responsibilities (internal vs external)
– Description of data and safety review process
– Time table for submission of data, safety, and progress
information
– Process to implement closure/suspension when significant
risks/benefits are identified
– Description of adverse event reporting procedures
40
 Elements of the Protocol (continued)
• Supportive care • Adverse events
• Pharmaceutical info – List (labs vs. symptoms)
– Procurement/supply – Reporting requirements
– Preparation – Data & safety monitoring
– Storage & stability plan
– Administration route • Response criteria
– Adverse effects
– Drug interactions
• On study procedures
– Registration
– Randomization
– Stratification factors
 Common Oncology Trial
Endpoints/Outcomes
• Overall survival • Durable complete
• Progression free survival response
• Time to progression • Partial response
• Time to treatment • Overall response rate
failure • Stable disease
• Disease specific survival • Progressive disease
• Complete response • Biomarker based
 Elements of the Protocol (continued)
• Supportive care • Adverse events
• Pharmaceutical info – List (labs vs. symptoms)
– Procurement/supply – Reporting requirements
– Preparation – Data & safety monitoring
– Storage & stability plan
– Administration route • Response criteria
– Adverse effects • Schedule of
– Drug interactions events/procedures
• On study procedures • Off study criteria
– Registration • Correlative studies (e.g.
– Randomization biomarkers, pk, etc.)
– Stratification factors
 Elements of the Protocol (continued)
• Statistical • Records retention
considerations guidelines
– Randomization (+/- • References
stratification)
• Informed consent
– Sample size (power
analysis) • Appendices
– Accrual rate (duration) – e.g. eligibility checklist,
– Analytic plan (primary toxicity monitoring
criteria, tumor response
and other objectives)
criteria, lists of
– Expected outcomes
interacting drugs,
– Interim analysis questionnaires, etc.
– Stopping rules
 Elements of the Protocol (continued)
• Amendments
– Summary of changes in front of protocol or as a stand
alone document
– Revised protocol must be approved by IRB (and PRMC)
before implementation
– General types
• Safety notice
• General requests
• Action letters
I have great idea & strategy but do I have…….

• The appropriate patient population

• Collaborating within and interdisciplinary
faculty
• Facilities/Cores to conduct the study
• Supportive clinical staff
• Time/administrative buy in
• Funding
• Legal/contractual issues
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NIH/NIGMS Award Number U54GM104942
West Virginia Clinical and Translational Science Institute