How to review a clinical research protocol for study feasibility assessment and clinical trial management. .

1. Clinical Trial Protocol
Ying Lu, MD, PhD
UC Davis Medical Center
June 2012

2. Read & Understand
Research Protocols
Objective
2

3. • Introduction to a
Research Protocol
• Review a Protocol
for Study Feasibility
Analysis
Presentation Outline
3

4. Clinical Research Protocol
4

5. 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

6. Protocol
Contents
6

7. • 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

8. 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

9. Protocol
Amendments
9

10. • 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

11. 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

12. Standard of Care vs.
Clinical Research
12

13. 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

14. Objectives/Endpoints
Surrogate Endpoints
Biomarkers
14

15. » 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

16. 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

17. ˃ 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
17

18. Protocol Contents
18

19. Study Design
19

20. 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

21. 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

22. Correlation Between Development Phase & Types of Study
Study Phases of Clinical Drug Development (ICH E8) 22

23. 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

24. 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

25. 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

26. Protocol Contents
26

27. Protocol Contents cont.
27

28. Inclusion/Exclusion
Criteria
28

29. 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

30. Protocol Contents cont.
30

31. Visits/Procedures
31

32. A study required intervention and assessments
plan, which may include:
˃ laboratory sample collections
˃ radiology
˃ biopsy
˃ other procedures
˃ physical examinations
˃ questionnaires
Visits/Procedures
32

33. 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

34. Visits/Procedures e.g..
34

35. Protocol Contents cont.
surgery
surgery
35

36. Adverse Events
36

37. Protocol Contents cont.
37

38. A Protocol Deviation
38

39. » 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

40. » 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

41. » 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

42. • Introduction to a
Research Protocol
• Review a Protocol
for Study Feasibility
Analysis
Presentation Outline
42

43. 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

44. »Scientific
»Financial
»Practical
Protocol Assessment
44

45. » 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

46. Protocol Contents
46

47. AssessmentoftheprotocolScientificMerit
47

48. » 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

49. » 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

50. 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

51. Assessing a Protocol for
Recruitment & Retention
51

52. Factors impeding enrollment
– type of disease
– enrollment period
– number of study subjects
– inclusion/exclusion criteria
– concomitant medications and /or treatment
– vulnerable populations
Recruitment
52

53. Factors impeding retention
˃ treatment methods
˃ side effects
˃ patient requirements restrictions
˃ study visit frequency
˃ difficulty to follow procedures
˃ trial length
Retention
53

54. AssessmentoftheprotocolEnrollment
Comment on whether factors will discourage
consent from parent or child
54

55. Protocol Contents cont.
55

56. • 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

57. 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

58. 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

59. 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

60. 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

61. 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

62. 62

63. The End
63ying.lu@ucdmc.ucdavis.edu
http://yingluca.blogspot.com/