clinical trial protocol review for study feasibility analysis
TRANSCRIPT
Clinical Trial Protocol
Ying Lu, MD, PhD
UC Davis Medical Center
June 2012
Read & Understand Research Protocols
Objective
2
• Introduction to a Research Protocol
• Review a Protocol for Study Feasibility Analysis
Presentation Outline
3
Clinical Research Protocol
4
1. Describes why the trial is being conducted
2. Rationale for the trial
3. The objectives (measured by endpoints)
4. How the trial will be executed
5. Procedures and measurements to evaluate the safety and effectiveness of a testing article
6. Meet regulatory requirements
A Protocol
5
Protocol Contents
6
• Title page • Protocol summary (synopsis) • Abstract (optional) • Table of contents • Introduction/background • Study objectives • Study design • Randomization and blinding • Subject selection • Subject enrollment • Informed consent • Screening procedures
• Replacement of subjects • Treatment • Concomitant medication • Study activities • Adverse events • Data recording instructions • Data quality assurance • Analysis plan • Risks and benefits • References • Appendices
FDA GCP Guidance
7
e.g.,
A Phase 2 Double-blind Parallel Trial of Dose Tolerance, Safety, and Efficacy Comparing Drug A to Placebo in Controlling Symptoms of Mild to Moderate Hypertension
Controlled, Randomized, Prospective, Double-Blind, Multicenter, Phase I/II, Dose-Escalation Study of the Safety, PK, and Clinical Activity of "XYZ" for Prophylaxis of Infection in Patients Undergoing Open Heart Surgery
The Protocol Title
stage design
indication population
drug
Protocol Amendments
9
• Amendment is a change(s) to or formal clarification of a protocol
• If changes (amendments) are made to the approved protocol
An amendment must be submitted to the IRB
New procedures only can be implemented after the IRB approval
Protocol amendment for IND (21 CFR 312.30) and IDE (21 CFR 812.35)
Protocol Amendments
10
e.g., protocol amendment for additional endocrine tests on visit 14 and 15
Protocol Amendments cont.
SDD, study drug discontinuation; PPW, premature patient withdrawal
e.g., The total amount of blood to be collected per subject is approximated 276 280 mL.
11
Standard of Care vs. Clinical Research
12
Standard of Care » Practice guidelines or knowledge of medical treatment.
Often, physicians also base interventions on the philosophy that making the patients feel better through comfort, reassurance, and education is as important as or more important than whether the clinical outcome is improved.
Clinical Research » The goal of a clinical trial is not directly to maximize
benefit to the patients in the trial but rather to discover whether a treatment is effective and safe.
Standard of Care vs. Clinical Research
13
Objectives/Endpoints
Surrogate Endpoints
Biomarkers
14
» Objectives are often stated as primary and secondary endpoints to be tested
» A clinical endpoint should be ˃ relevant and easy to interpret
˃ clinically apparent and easy to identify
˃ sensitive to treatment differences e.g.,
Primary Endpoints:
• To determine the safety and dose-limiting toxicities (DLTs) of "XYZ" when administered as a single intravenous push (IVP) to patients undergoing deceased donor kidney transplant.
Secondary Endpoints:
• To prospectively determine the feasibility and validity of additional efficacy endpoints in this study population.
Objectives
15
Measurements of the potential effects (outcomes) of the study intervention, such as
Death,
Stroke,
Re-hospitalization,
Tumor regression/size,
Quality of life (e.g., health survey question form SF-36)
Endpoints
16
˃ Physiological markers or biomarkers closely correlated with the clinical endpoints
˃ May be used to substitute for an undesirable or rare primary endpoints
˃ May not have one-to-one guaranteed relationship with the clinical outcome
˃ Examples of biomarkers as surrogate endpoints: LDL (low density lipoprotein cholesterol) – coronary disease
CRP (C-reactive protein) – inflammation status
GFR (glomerular filtration rate) – renal function, safety
ECG, blood pressure
PK, PD
Surrogate Endpoints
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Protocol Contents
18
Study Design
19
Type of study (pilot, PK, tolerance, etc.)
» Controlled or uncontrolled
» Single or multiple dose (fixed or variable)
» Single site or multicenter
» Open label or blinded
» Randomization scheme
» Design (paralleled, crossover, sequential, etc.)
Study Design
20
Phase l (Human pharmacology) e.g., pharmacokinetics study of a single dose of test drug A in healthy volunteers
Phase II (Therapeutic exploratory) e.g., A double-blind study evaluating the safety and efficacy of 1 mg/kg Test Drug "A" versus placebo in disease-state patients
Phase III (Therapeutic confirmatory) e.g., A study of the relative safety and efficacy of test Drug A versus Marketed Drug B in a disease state
Phase IV (Therapeutic use) e.g., the pharmacoeconomics of short-term treatment with approved drug A versus approved drug B in disease-state patients
Post-marketing survey
ICH E8
Clinical Drug Development Phases
21
Correlation Between Development Phase & Types of Study
Study Phases of Clinical Drug Development (ICH E8) 22
e.g., Controlled trial design • Matched pairs
• Parallel
• Crossover
– blinded sequence with an washout period
– subject serves as his/her own control (before/after)
• Group comparisons
• Mixed design
• Factorial
Study Design
ICH-E9 Statistical Principles for Clinical Trials
23
Blinding ˃ Avoidance of conscious or subconscious influence
˃ Fair evaluation outcomes
Types of Blinding (ICH E9) ˃ Open-label (un-blinded, common in Phase I trials)
˃ Single-blind
˃ Double-blind (ethical considerations)
˃ Double-dummy
Blinding
ICH-E9 Statistical Principles for Clinical Trials
24
Random Sampling • A chance determines who will
be in the sample
Randomization • A chance determines the assignment of the treatment arms
• Each participant has the same chance of receiving any of the interventions
• Random treatment assignments are performed to reduce bias
• Randomization process may use interactive voice response system, online, local pharmacy.
Random Sampling & Randomization Process
ICH-E9 Statistical Principles for Clinical Trials
25
Protocol Contents
26
Protocol Contents cont.
27
Inclusion/Exclusion Criteria
28
Criteria of including and excluding the study target population, typically related to: ˃ Characteristics of subjects, disease and treatment
˃ Subject age
˃ Pre-existing history and conditions
˃ Reproductive capability
˃ Screening laboratory values
˃ Participating in another clinical trial
˃ Ability to fully cooperate study procedures
˃ Willing to give informed consent
Inclusion/Exclusion Criteria
29
Protocol Contents cont.
30
Visits/Procedures
31
A study required intervention and assessments plan, which may include:
˃ laboratory sample collections
˃ radiology
˃ biopsy
˃ other procedures
˃ physical examinations
˃ questionnaires
Visits/Procedures
32
Specific procedures, such as » Withdrawn by the investigator for safety reasons
» Subject replacement for withdrawn, dropped out, lost to follow-up
» Protocol-required follow-up procedures and tests for withdrawn subjects
Visits/Procedures cont.
33
Visits/Procedures e.g..
34
Protocol Contents cont.
surgery
surgery
35
Adverse Events
36
Protocol Contents cont.
37
A Protocol Deviation
38
» The investigator may implement a deviation from, or a change in, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favorable opinion.
» As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted: ˃ (a) To the IRB for review and approval/favorable opinion;
˃ (b) To the sponsor for agreement and, if required;
˃ (c) To the regulatory authority(ies).
Protocol Deviation From an IRB Approved Study
39
» Equipment failures during study procedures
» the use of the wrong version of a form (including invalidated consent forms)
» enrolling study participants who do not meet the approved inclusion criteria.
» e.g., The protocol excluded potential subjects who were taking Aleve (naproxen) medication one (1) month prior to the screening visit. The Medical Information Sheet for subject XX at screening documents that the subject was currently taking Aleve; however, the subject was randomized in violation of the protocol.
» protocol deviations are considered serious when
˃ they create increased risks to participants,
˃ adversely affect the rights and welfare of participants, or
˃ affect the scientific integrity of a study
Deviation e.g.,
40
» Protocol & protocol amendment
» Standard of care vs. clinical research
» Objective, endpoints, surrogate endpoints, & biomarkers
» Study design ˃ development phases,
˃ types of controlled studies,
˃ blinding & randomization,
˃ inclusion/exclusion criteria,
˃ study visit & assessment schedules,
» protocol deviation
Introduction to a Research Protocol
41
• Introduction to a Research Protocol
• Review a Protocol for Study Feasibility Analysis
Presentation Outline
42
Research with Human Subjects
Scientific
methodology to answer the study
question
Medical
knowledge of targeted
disease and its condition
Ethics
to protect the research
subjects from harm
43
»Scientific
»Financial
»Practical
Protocol Assessment
44
» Does the study address a question of clinical and scientific relevance?
» Is the study likely to achieve its scientific goals?
» Are there any ethical considerations ? e.g., any risk to subjects
» What impact will the study have on patients ?
e.g., will extra investigations be required
Protocol Assessment -- Scientific
45
Protocol Contents
46
Ass
essm
ent
of
the
pro
toco
l Sci
enti
fic
Mer
it
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» What are the local costs of participating ?
˃ pharmacy and laboratory costs,
˃ cost of staff training
» What will be the cost of staff for time spent conducting the study at the study site?
» What is the payment schedule?
Protocol Assessment -- Financial
48
» Can the sample size be achieved in the available time?
» Are the eligibility criteria realistic?
» What are the procedures for data collection and processing?
» Do you have the necessary staff to perform the trial?
» Are there any special investigations or equipment(s) required?
Protocol Assessment -- Practical
49
CRC's task
» Understand the clinical and scientific importance of the study and explain the study clearly to others
» Determine if the study is likely to be acceptable to patients
» What impact the study might have on patients in terms of
˃ time, commitment, risk, and inconvenience.
Protocol Assessment
50
Assessing a Protocol for Recruitment & Retention
51
Factors impeding enrollment – type of disease
– enrollment period
– number of study subjects
– inclusion/exclusion criteria
– concomitant medications and /or treatment
– vulnerable populations
Recruitment
52
Factors impeding retention
˃ treatment methods
˃ side effects
˃ patient requirements restrictions
˃ study visit frequency
˃ difficulty to follow procedures
˃ trial length
Retention
53
Ass
essm
ent
of
the
pro
toco
l En
rollm
ent
Comment on whether factors will discourage consent from parent or child
54
Protocol Contents cont.
55
• Margaret Liu and Kate Davis, A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons from a Horse Named Jim, 2010
• Deborrah Norris. Clinical Research Coordinator Handbook, Fourth Edition, 2009
• Carol A Fedor., Responsible Research: A Guide For Coordinators, 2006
• ICH-E6 (GCP), ICH-E8
• UC Davis Clinical Research Guidebook, 2012
Reference
56
A CRC is reviewing a protocol for a Phase I study. The objective for conducting the study could be to determine the A. safety and efficacy of chemotherapy agent "X" versus placebo in
alleviating pain in osteoarthritis patients.
B. dose of best investigational product in reducing soft tissue inflammation following third molar extractions.
C. dose at which caffeine enhances acetylsalicylic acid absorption in normal, healthy volunteers.
D. blood levels of acetaminophen in post-partum patients when taken on an empty stomach versus two hours after meal consumption.
Quiz 1
57
A subject is participating in a clinical trial where only the CRC knows the identity of the study medication. This is considered to be which of the following types of studies? A. crossover
B. Open-label
C. Single-blind
D. Placebo-controlled
Quiz 2
58
Which of the following is a well-defined clinical study using a placebo to evaluated the treatment group?
A. Open-label
B. retrospective
C. controlled
D. active concurrent controlled
Quiz 3
59
When reviewing a protocol, the schedule of study events would most likely be presented
A. in the protocol text
B. by referring to the events section of the study manual
C. as a table appended to the protocol
D. in the informed consent form
Quiz 4
60
An untoward medical occurrence that was not evident during baseline is considered to be
A. A pre-exiting condition ?
B. An adverse event ?
C. Associated with the use of the test article ?
D. Unexpected ?
Quiz 5
61
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