overview of clinical research, (Clinical Trial Phase-0,1,2,3 & 4), ICH etc.,

1. Swaroop14/10/13 1
Prepared By
Swaroop Kumar Koduri,
swaroopkumar@lupin.com
swarooppharmacology@gmail.com

2. • Clinical trials are a set of tests in medical
research and drug development that
generate safety and efficacy data for health
interventions in human beings.
• Clinical trials are conducted only after
satisfactory information has been gathered
on the quality of the nonclinical safety, and
health authority/ethics committee approval
is granted in the country where approval of the drug or device is
sought.
• Clinical Trials are “real world” applications of the Scientific Method.
Introduction
swaroop14/10/13 2

3. • Involve in vitro (test tube or laboratory) studies and trials on
animal populations.
• Wide ranging dosages of the compounds are introduced to
the animal subjects or to an in vitro substrate.
• Obtain preliminary efficacy and pharmacokinetic information.
• Decisions are made during this phase regarding further
development of the test compound, test item, or test article.
Pre-clinical Phase
swaroop14/10/13 3

4. • Based on researchers behave
– Observational study
– Interventional study
• Based on the purpose (National Institutes of Health)
– Prevention trials
– Screening trials
– Diagnostic trials
– Treatment trials
– Quality of Life
Types of Clinical Trials
swaroop14/10/13 4

5. • 1. Preclinical (animal) testing.
• 2. An investigational new drug application (IND) outlines what
the sponsor of a new drug proposes for human testing in
clinical trials.
• 3. Phase 1 studies
• 4. Phase 2 studies
• 5. Phase 3 studies
• 6. The pre-NDA period, just before a new drug application
(NDA) is submitted.
• 7. Submission of an NDA is the formal step asking the FDA to
consider a drug for marketing approval.
• FDA reviewers will approve the application or find it either
"approvable" or "not approvable."
Drug Review Steps
swaroop14/10/13 5

6. Clinical Trial
swaroop14/10/13 6

7. Complete Adaptive Trials Management
swaroop14/10/13 7

8. Overview Of Clinical Trials
swaroop14/10/13 8

9. 1. Early research and preclinical testing
2. IND application filed with FDA
3. Clinical trials (phases 1, 2, and 3)
4. NDA filed with FDA
5. FDA validates claim and approves drug
The Drug Development and Approval Process
swaroop14/10/13 9

10. Types of Clinical Trials
Based on
researchers
behave
Based on the
purpose
•Observational study
•Interventional study
•Prevention trials
•Screening and early detection
trials
•Diagnostic trials
•Treatment trials
•Genetics trials
•Quality of Life / supportive care
•Compassionate use trials
swaroop14/10/13 10

11. • Phase 1: 15-30 people
– What dosage is safe?
– How should treatment be given?
– How does treatment affect the body?
• Phase 2: Less than 100 people
– Does treatment do what it is supposed to?
– How does treatment affect the body?
• Phase 3: From 100 to thousands of people
– Compare new treatment with current standard
• Phase 4: From hundreds to thousands of people
– Usually takes place after drug is approved
– Used to further evaluate long-term safety and effectiveness of
new treatment
Phases of Clinical Trials
swaroop14/10/13 11

12. Human micro dosing studies
Exploratory IND studies by FDA
It is an important element of NEXT. It promises to shorten the
timeline by upto 6-12 months
MICRO DOSE: Less than1/100 of the dose of a test substance
calculated to yield pharmacological effect of the test substance
with a max dose of <100 micrograms
Patients Typically very small numbers of patients are involved.
(10-15)
These are very early studies of the pharmacodynamic and
pharmacokinetic properties of a potential drug in humans.
Phase 0
swaroop14/10/13 12

13. ADVANTAGES:
Microdose is used so, ADE are less
Short duration
Inexpensive
Useful in the discovery of endogenous biomarkers
LIMITATIONS:
Limited use of agents having Non linear PKs
Agents having different kinetic characteristics between
microdose and full dose are not evaluated by phase 0 trials.
The laboratory parameters are very limited and expensive,
researchers have to depend on BA/BE labs.
Phase 0
swaroop14/10/13 13

14. • The aim of a Phase I trial is to determine the maximum tolerated
dose (MTD) of the new treatment. The MTD is found by escalating
the treatment dose until the dose-limiting toxicity (DLT) is reached.
• Designed to assess the safety, tolerability, PK and PD of drug.
• 20-25 healthy volunteers
• Patients: Anticancer drugs, AIDS therapy
• Duration: 6-12 months
• No blinding
• Kinds of Phase I
 SAD
 MAD
 Food effect
Phase 1
swaroop14/10/13 14

15. 3 pts
Dose
3 pts
3 pts
3 pts
3 pts
3 ptsRecommended dose
DLT
Starting dose
3 pts+ DLT
Phase I Standard 3 + 3 Design
swaroop14/10/13 15

16. Pre-IND meetings with the sponsor
(although not a requirement)
IND submission
Non-Clinical Review Clinical Review
Pharm/ToxCMC
Review for Phase 1 Trials

17. • First in patients
• Duration: 6 months to several years.
• It acts as a screening stage.
• To evaluate activity, safety and feasibility of the new treatmen
Therapeutic Exploratory Trial. (20-300 Subjects).
Efficacy in patients (primary objective)
Safety issues (secondary objective)
Optimum dose finding
Phase II
Phase IIA
Phases IIB
Phase II
swaroop14/10/13 17

18.  Phase IIa
 Designed to assess dosing
requirements
 EARLY PHASE
 Pilot clinical trials
 20-200 PATIENTS
 SINGLE BLIND comparison
with a standard drug
 Phase IIb
 Designed to study efficacy
 LATE PHASE
 Pivotal clinical trials
 50-300 PATIENTS
 DOUBLE BLIND compared
with a placebo or standard
drug
Phase II
swaroop14/10/13 18

19. • Large scale, Randomised, Controlled trials . Minimises errors of phases I
and II.
• To establish efficacy of the drug against existing therapy in larger number of
patients, method of usage etc.,.
• To compare the new treatment against a suitable comparator.
• Target population: several 100’s to 3000 patients. Takes a long time: up to 5
years
Phase III
swaroop14/10/13 19

20. • Phase IIIa
• To get sufficient and significant
data.
• Prior to NDA
• Generates data on safety and
efficacy in both controlled and
uncontrolled trials.
• Provides much of information
for the package insert
• Phase IIIb
• Allows patients to continue the
treatment, Label expansion, additional
safety data.
• After the NDA but prior to the approval
and launch.
• Period between submission and
approval of a regulatory dossier for
marketing authorization
• These may supplement or complete the
earlier trials or may be directed to Phase
IV trials.
Phase III
swaroop14/10/13 20

21.  No fixed duration / patient population
 Starts immediately after marketing
 These are primarily observational or non- experimental in nature.
 Helps to detect rare ADRs, Drug interactions
 Also new uses for drugs [Sometimes called Phase V]
 Harmful effects discovered may result in a drug being no longer sold,
or restricted to certain uses.
 Involves safety surveillance.
 Determine behavior of drug in real life situations.
 Evaluate action of drug in a situation of missed dosage or over dosage.
Phase IV or Post marketing Surveillance
swaroop14/10/13 21

22. Regulator
Sponsor
CRO
CRA
Project
Manager
Medical
Director
Regulatory
Personnel
Investigator/Sub-
Investigator
CRA
Subjects
IRB
Players in Clinical Trials
swaroop14/10/13 22

23. Establishing an overall approach
Establishing clinical trial objectives
Choice of an overall clinical trial design
Choosing the clinical trial’s blind
Bias and confounding factors
Sample size and number of parts of a clinical trial
Randomization procedures
Screening, baseline, treatment and post treatment periods
Patient populations, methodologies and measurements
Patient recruitment
Dosing schedule
Dosage forms and formulations
Route of administrations
Compliance
Pharmacokinetics and medicine interactions
Data review committee
Factors considered in constructing a clinical study
swaroop14/10/13 23

24. • Perspectives
– Medical perspective
• Question(s) to be answered- objectives
– Marketing perspective
• Utility of data generated
– Regulatory perspective
• Regulatory guidance
– Political and social
• Companionate use, open label designs, parallel track,
interim analyses, early stopping etc
Choice of a design
swaroop14/10/13 24

25. • Pilot refers to the purpose of the trial
– E.g. dose ranging, POC, initial efficacy evaluation, new
indication, dry run, determinations of feasibility, protocol
refinements prior to large studies, clinical Pharmacology
variables etc)
• A well designed, controlled, conducted and analyzed pilot
trial- can be considered as a pivotal trial
Pilot Vs Pivotal trials
swaroop14/10/13 25

26. • Need for a clinical trial
• Least complex approach to address a clearly stated clinical
problem (depth and breadth)
• Which comes first- objectives or design
– Design- framework to meet objectives
– May need to refine objectives if design is difficult to
implement
Trial objectives
swaroop14/10/13 26

27. • Safety evaluation
• Pharmacokinetic evaluation
• Efficacy evaluation
• Mechanism of action evaluation
• General population evaluation
• Evaluation of clinical methodology
• Evaluation of clinical pharmacology
• Post marketing evaluations
Types of clinical trials of new medicines
swaroop14/10/13 27

28. • The choice of design depends on the goal of the trial
• Choice also depends on the population and knowledge of the
intervention
• Proper design is critical, analysis cannot rescue improper
design
Trial design
swaroop14/10/13 28

29. • Prospective/ retrospective
• Parallel/ Cross over
• Randomization
• Blinding
• Control
• Comparison
Design items
swaroop14/10/13 29

30. • Unless there are strong reasons, clinical trials should use
prospective designs
• Case-control studies-
– retrospective,
– starts with an outcome then traces back to investigate exposures
– measures the strength of the association between an exposure and
the outcome (odds ratio)
• Cohort studies
– prospective, retrospective or combination
– follows a group of people having common attribute
– uses correlations to determine the absolute risk
Prospective Vs Retrospective
swaroop14/10/13 30

31. Broad classification of studies
swaroop14/10/13 31

32. Parallel Vs cross over
swaroop14/10/13 32

33. Treatment group 1
Treatment group 2
Treatment group 3
Treatment group 1
Treatment group 2
Treatment group 3
Treatment group 4
Treatment group 5
Treatment group 6
Treatment group 7
Treatment group 8
Placebo
Treatment group 1
Treatment group 2
Treatment group 3
Common parallel
design
Two part parallel
design
Parallel design with Placebo
Initiation
Parallel Vs cross over (1)
swaroop14/10/13 33

34. Treatment 1
Treatment 2
Treatment 3
Treatment 1
Treatment 2
Treatment 3
Placebo
Placebo
Placebo
Placebo during treatment
Multiple doses within each treatment group
Treatment 2 Dose F
Dose BTreatment 1
Dose E
Dose A
Dose G
Dose C
Dose H
Dose D
Parallel evaluation of a combination medicine
Treatment A
Treatment B
Treatment A + B
Placebo
Parallel Vs cross over (2)
swaroop14/10/13 34

35. • Subjects are randomized to one of two or more arms, each
arm being allocated a different treatment
• Robust (missed visit, missing data)
• Allows between patient comparison and not within patient
• For same sample size, less sensitive than cross over but
shorter in duration
• Requires larger number of patients
• No period effect
Parallel Vs cross over (3)
swaroop14/10/13 35

36. Single cross over with no intervening baseline
Single cross over with intervening baseline
BL BL
Tr ATr A
Tr BTr B
BL BLTr ATr A
Tr BTr B
BL
Double cross over (earlier two
scenarios)
BL BL
Tr ATr A
Tr BTr B
Tr A
Tr B
Extra period cross over
Parallel Vs cross over (4)
swaroop14/10/13 36

37. • Each subject is randomized to a sequence of two or more treatments, and
hence acts as his own control for treatment comparisons
• Order of treatment is randomized
• Comparison is “within” patients not “between” patients
• Patient must complete both arms
• Drug must be short acting
• Outcome must be reversible
• Less number of patients, longer duration
• Adv- Smaller sample size reduced, Each patient their own control, less
number of assessments to achieve a specific power
• Dis adv-Possible carry over effect, Possible period effect, Not useful for
acute disease, Disease must be stable, difficulties in analysis (loss of
patients)
Cross over design (5)
swaroop14/10/13 37

38. • Facilitate the conduct of interim analysis
• More practical to assess grouped subject outcomes at
periodic intervals
• Most widely and successfully used in large, long-term trials of
mortality or major nonfatal endpoints
• Also being used for other safety endpoints
• Data can be analyzed in an open or blinded manner (IDMC)
Factorial design
swaroop14/10/13 38

39. • Two or more treatments are evaluated simultaneously
through the use of varying combinations of the treatments
– Simplest example is the 2×2 factorial design (balanced)
• A, B, A & B, neither A nor B
• Effective way of comparing multiple interventions
• Combine two or more studies in one study
• Allows studying the effect of each factor on the response
variable, as well as the effects of interactions between
factors on the response variable.
• It is assumed that there is no interaction between A and B
Group sequential design
swaroop14/10/13 39

40. • Also used
– To establish the dose-response characteristics of the
simultaneous use of two treatments
– To make efficient use of clinical trial subjects in high
mortality trials
• Adv:
– Cost, number of patients, evaluation of combination of
interventions
• Limitations
– Treatment interactions
– Compliance (several interventions)
Factorial design
swaroop14/10/13 40

41. • Often parallel design
• Latin square design (cross over)
– ABCD, BCDA, CDAB, DABC
• Each group receives each treatment
• Patient acts a self control
Multiple groups of patients
swaroop14/10/13 41

42. • Placebo run-in
• Compliance run-in
• No treatment run-in
Run-in period designs
swaroop14/10/13 42

43. Randomization and stratification
swaroop14/10/13 43

44. • Researchers assign patients by chance to either a group taking the new
diagnostic or treatment agent. Similar to “flipping a coin”.
• Randomization helps avoid bias.
• The assigned groups are often referred to as “arms”.
Example: Patient #1 is assigned to Arm A of the trial, which
involves the new modality or treatment. Patient #2 is assigned
to Arm B, which is the standard modality or treatment.
Randomization(1)
swaroop14/10/13 44

45. • Randomization introduces a deliberate element of chance into the
assignment of treatments to subjects in a clinical trial.
• A method used to prevent bias in research; a computer or a table of
random numbers generates treatment assignments, and participants have
an equal chance to be assigned to one of two or more groups (e.g., the
control group or the investigational group)
• Benefits
– Maximized statistical power (esp. in subgroup analysis)
– Minimizes selection bias
– Minimizes allocation bias (wrt. Covariates)
• Limitations –
– Divergent baselines
– Does not ensure equal distribution of risk factors or other patient
characteristics (stratification helps here)
Randomization(2)
swaroop14/10/13 45

46. Randomization(3)
swaroop14/10/13 46

47. • Simple randomization
• Block randomization
– Adv-equal distribution, particularly when subject characteristics may
change over time
• Systematic randomization
– Order in first block, repeated
– Sequential assignment
• Stratification
– E.g. By site
• Minimization
– All factors likely to impact are considered, central site, managed by
computer program
• Other variations
– Quota
– Use of clinical index
– Sites, communities, geographies etc
• Obtaining and using randomization codes
Randomization-Types (4)
swaroop14/10/13 47

48. • Categorizing subjects into subgroups by specific
characteristics
– Enables researchers to look into separate subgroups to
see whether differences exist
Stratification (1)
swaroop14/10/13 48

49. Stratification (2)
swaroop14/10/13 49

50. Blinding
swaroop14/10/13 50

51. • Blinding or masking is intended to limit the occurrence of
conscious and unconscious bias in the conduct and
interpretation of a clinical trial arising from the influence
which the knowledge of treatment may have on the
recruitment and allocation of subjects, their subsequent care,
the attitudes of subjects to the treatments, the assessment of
end-points, the handling of withdrawals, the exclusion of data
from analysis, and so on.
Blinding
swaroop14/10/13 51

52. • In a single blinded study, the patient does not know which
arm of the protocol they have been assigned to.
• This approach avoids bias because when people know what
they are taking, it might change the way they react.
Example: Patients who know that they are assigned to
the “new treatment” group might expect it to work better
and report hopeful signs because they want to believe they
are getting well. This could bias the study by making
results look better than they are.
What is a Blinded Study?
swaroop14/10/13 52

53. • Double blinded studies are those studies where neither the
patient or the research physician know whether the patient is
receiving the actual study drug or standard drug.
• When no standard is available, some studies compare new
drugs with placebo drugs.
• All patients are informed of the possibility of being assigned
to the placebo arm of a study
• Patients are “unblinded” only if it becomes medically
necessary prior to the end of the study.
Blinded Trials cont…
swaroop14/10/13 53

54. • Traditional definitions
– Open label
– Single blind
– Double blind
– Combination of blinds
Blinding (1)
swaroop14/10/13 54

55. • New definitions
– Full double blind
• Patient and every one who interacts with the patient
– Full triple blind
• Monitor/ statistician
– Quadruple blind
• Statistician
– Full clinical trial blind
• Patient and every one who interacts with the patient and data
Blinding (2)
swaroop14/10/13 55

56. • Difficult situations
– Treatments of two different nature
• Surgery and medical therapy
• Different formulations
• Pattern of administration
– (Double dummy)
• Treatment induced effects
– Two physicians method
• Placebo of a marketed medicine
– Use generic if available, two physician method
– Tablet in capsule
» Dissolution?, New IND
– Coordinator administers the drug
– Wrapping of infusion bottles
Maintaining blinding (3)
swaroop14/10/13 56

57. Control groups
swaroop14/10/13 57

58. • To allow discrimination of patient outcomes caused
by experimental intervention from those caused by
other factors
– Natural progression of disease
– Observer/patient expectations
– Other treatment
• Fair comparisons
– Necessary to be informative
Control groups (1)
swaroop14/10/13 58

59. • Choice
– Goals of Controlled Clinical Trials
– Types of Control Groups
– Significance of Control Group
– Assay Sensitivity
Control groups (2)
swaroop14/10/13 59

60. • Available standard therapies
• Adequacy of the control evidence for the chosen
design
• Ethical considerations
Considerations in Choice of Control Groups (3)
swaroop14/10/13 60

61. • 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
Significance of Control Group (4)
swaroop14/10/13 61

62. • External
– Historical
– Concurrent, not randomized
• Internal and concurrent
– No treatment
– Placebo
– Dose-response
– Active (Positive) control
• Multiple
– Both an Active and Placebo
– Multiple doses of test drug and of an active control
Type of Controls (5)
swaroop14/10/13 62

63. • The “placebo effect” is well documented
• Could be
– No treatment + placebo
– Standard care + placebo
• Matched placebos are necessary so patients and investigators
cannot decode the treatment
Use of Placebo Control (6)
swaroop14/10/13 63

64. • A new treatment used in a series of subjects
• Outcome compared with previous series of comparable
subjects
• Non-randomized, non-concurrent
• Rapid, inexpensive, good for initial testing of new treatments
• Two sources of historical control data:
• Literature  Subject to publication bias
• Data base
Historical Control (1)
swaroop14/10/13 64

65. • Vulnerable to bias
• Changes in outcome over time may come from change in:
– underlying patient populations
– criteria for selecting patients
– patient care and management peripheral to treatment
– diagnostic or evaluating criteria
– quality of data available
Historical Control (2)
swaroop14/10/13 65

66. • Tend to exaggerate the value of a new treatment
• Literature controls particularly poor
• Even historical controls from a previous trial in the same
institution or organization may still be problematic
• Adjustment for patient selection may be made, but all other
biases will remain
Historical Control (3)
swaroop14/10/13 66

67. • Not randomized
• Patients compared, treated by different strategies, same
period
• Advantage
– Eliminate time trend
– Data of comparable quality
• Disadvantage
– Selection Bias
– Treatment groups not comparable
• Covariance analysis not adequate
Concurrent Controls
swaroop14/10/13 67

68. • Types
• Magnitude of effects
• False positive
• Sources
• Patient selection
• Referral patterns
• Refusals
• Different eligibility criteria
• Experimental environment
• Diagnosis/staging
• Supportive care
• Evaluation methods
• Data quality
Biases in Concurrent Control Study
swaroop14/10/13 68

69. Absence of a control group
• Advantages
– Used to generate hypothesis and can provide
justification for large scale trials
– PK properties of novel drugs
– Sometimes only design for ethical reasons (surgical
procedures)
• Limitations
– Susceptible to investigator bias
– Susceptible to over-interpretations
– Generate less information
Uncontrolled trials
swaroop14/10/13 69

70. COMPARISON
swaroop14/10/13 70

71. • Superiority
– Efficacy is established by showing superiority over
placebo, active control, or dose response
– Used for serious conditions
• Equivalence or Non-inferiority
– Equivalence
• Bio-equivalence
• Clinical equivalence
– Non inferiority
• Dose-response Relationship
Types of comparison
swaroop14/10/13 71

72. • Branch of Medical Science.
• Systematic, observational and experimental biomedical
studies.
• Ultimate goal is to improve the Quality of Life (QoL).
Clinical Research
swaroop14/10/13 72

73. • One form of Clinical research
• Systematic experimental Biomedical studies.
• To evaluate the effectiveness and safety of
medications or medical devices or biologics
etc.,.
Clinical Trail
swaroop14/10/13 73

74. • New techniques for screening and diagnosing a
disease.
• New drugs to market.
• New methods for surgery.
• New approach for radiation therapy.
• New combination of standard treatments.
• New techniques, such as Gene therapy
Importance of Research
swaroop14/10/13 74

75. Written plan for how the drug is to be studied and the procedures
to be followed by each investigator
Clinical Trial Protocol
A written, detailed action plan that:
Provides background about the trial
Specifies trial objectives
Describes trial’s design and organization
Ensures that trial procedures are consistently carried
out
What is a Clinical Protocol
swaroop14/10/13 75

76. • Eligibility criteria: Can range from general (age, sex, type of
cancer) to specific (prior treatment, tumor characteristics, blood
cell counts, organ function); eligibility criteria also vary with trial
phase
– Varies with protocol and phases
• Endpoint: Measurable outcome that indicates an intervention’s
effectiveness
• Randomization: A method used to prevent bias in research; a
computer or a table of random numbers generates treatment
assignments, and participants have an equal chance to be
assigned to one of two or more groups (e.g., the control group
or the investigational group)
Clinical Trial Design
swaroop14/10/13 76

77. • Belmont Report
– Ethical Principals in Human Subjects Review
– Respect, Beneficence, Justice
• International Conference of Harmonisation (ICH)
– Brings together the regulatory authorities of Europe, Japan, and the
US to discuss scientific aspects of human research.
• Good Clinical Practices (GCP)
-- Defines the roles and responsibilities of clinical trial sponsors,
investigators, and monitors.
• Declaration of Helsinki
– was developed by the World Medical Association] (WMA), as a set of
ethical principles for the medical community regarding human
experimentation
• Nuremburg Code
– set of principles for human experimentation set as a result of the Nuremberg Trials at
the end of the second world war. Specifically, they were in response to the inhumane
Nazi human experimentation carried out during the war by individuals such as Dr. Josef
Mengele.
Human Subject Protection Guidelines
swaroop14/10/13 77

78. • A group of scientists, doctors, clergy, and consumers
• All clinical trials must be reviewed and approved by your local Institutional
Review Board (IRB). The IRB reviews the protocol and patient consent to
make sure the study is conducted fairly and participants are not likely to
be harmed.
• The IRB also decides how often to review the trial once it has begun. They
also decide whether the trial should continue as initially planned and what
changes should be made.
• An IRB can stop a clinical trial if there are safety concerns, inappropriate
trial oversight, or if evidence becomes available that a new intervention is
effective, in order to make it widely available.
Institutional Review Board
swaroop14/10/13 78

79. FDA Requirements
• Must have at least 5 members
• If studies include vulnerable populations, the IRB should have
members who are familiar with these groups.
• Should include both men and women.
• Members should NOT be all of the same profession.
• Must include at least one scientist and one non-scientist
• Must include at least one person who is not affiliated with the
institution, sometimes called “community members”.
• Members may not vote on their own projects.
• Only actual IRB members may vote (consultant may be used
but can not vote).
Members in IRB
swaroop14/10/13 79

80. • The process in which a patient learns key facts about a
research study and then voluntarily agrees to take part or
decides against it.
• Informed consent must be documented by the use of a
written consent form approved by the IRB for all ACRIN
studies.
• Consent forms must be signed by the subject or the subject’s
legally authorized representative.
• A copy shall be given to the person signing the form.
Informed Consent
swaroop14/10/13 80

81. • The consent form MUST include the following:
– Statement that the study involves research
– Explanation of the purposes
– Expected duration of the subject’s participation
– Description of the procedures involved in the study
– Identification of any procedures that are experimental
– Risks or discomforts
– Benefits
– Alternatives to the research study
– Statement of confidentiality
– Statement about medical care and compensation should injury occur
– Contact information for patients with concerns or questions
– Statement that participation is voluntary and study withdrawal may
take place at any time
Consent Form Requirements
swaroop14/10/13 81

82. • Principal Investigator
• Authorized Study Personnel
– RA
– RN
– Research Coordinator / Designated Research Staff
 An IRB may waive the requirement for the investigator to
obtain a signed consent form if…
– The research presents no more than minimal risk of harm
to subjects and involves no procedures for which written
consent is normally required outside of the research
context
Who obtains written informed consent?
swaroop14/10/13 82

83. Physicians and other health professionals may:
• Be unaware of appropriate trials
• Be unwilling to lose control of patient’s care
• Believe that standard therapy is best
• Believe that clinical trials are more work
• Harbor concerns about the patient’s care or how the person
will react to suggestion of clinical trial participation
Barriers to Adult Participation in Clinical Trials
swaroop14/10/13 83

84. Patients may:
• Be unaware of clinical trials
• Lack access to trials
• Fear, distrust, or be suspicious of research
• Have practical or personal obstacles
• Face insurance or cost problems
• Be unwilling to go against their physicians’ wishes
Barriers to Adult Participation in Clinical Trials
swaroop14/10/13 84

85. • Early access to new treatments
• Active role in own health care
• Participation in advancing medical knowledge
Benefits of Participating in Clinical Trials
swaroop14/10/13 85

86. • New treatments are not always better than standard
care
• Unexpected side effects
• May not work for everyone
• Additional cost
Trials Risks of Participating in Clinical Trials
swaroop14/10/13 86

87. Study
Design
Design
Study
Documents
Notification
to Regulatory
Authority
Investigator
Selection
Ethics
Committee
Review
Approval
Letter
Investigator
Meeting
Site
Initiation
Patient
Enrollment
Monitoring
Data
Management
Follow up
Visits
End of
Trial
Statistical
Review
Final
Report
Overview of Clinical Trial
swaroop14/10/13 87

88. • Depends on the kind of trial being conducted.
• Includes Doctors (Investigators), nurses, health care
professionals etc.,
• Monitors the participants carefully during the trial and stay in
touch after the trial is completed.
• CT, successful when the protocol is carefully followed.
• Some trials involves interviews, questionnaires or surveys of
interventional treatment.
What Happens During the Clinical Trial
swaroop14/10/13 88

89. Course of events for a clinical trial
swaroop14/10/13 89

90. Summary of various phases
swaroop14/10/13 90

91. • Definition of Source Document/Data
All information in original records and certified copies of original
records of clinical findings, observations, or other activities in a
clinical trial necessary for the reconstruction and evaluation of the
trial.
• Original documents or certified copies can include the following:
• Hospital records
• Clinic and office chart records
• Laboratory notes
• Patient diaries
• Pharmacy dispensing records
• Photographic negatives
• X-rays
SOURCE DOCUMENTS
swaroop14/10/13 91

92. ICH
The complete name of ICH is the “International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use”.
ICH is a joint initiative involving both regulators and research-based industry
representatives of the EU, Japan and the US in scientific and technical discussions of the
testing procedures required to assess and ensure the safety, quality and efficacy of
medicines.
The International Conference on Harmonisation of Technical Requirements for the
Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint
regulatory/industry project to improve, through harmonisation, the efficiency of the process
for developing and registering new medicinal products in Europe, Japan and the United
States, in order to make these products available to patients with a minimum of delay.
swaroop14/10/13 92

93. The six parties to ICH represent the regulatory bodies and research-based industry in the
three regions, Europe, Japan and the USA, where the vast majority of new medicines are
currently developed
The objective of ICH is to increase international harmonization of technical
requirements to ensure that safe, effective, and high quality medicines are developed and
registered in the most efficient and cost effective manner
swaroop14/10/13 93

94. The ICH Topics are divided into four major categories and ICH Topic Codes are
assigned according to these categories.
Q S E M
"Quality" Topics,
i.e., those relating
to chemical and
pharmaceutical
Quality
Assurance
(Stability Testing,
Impurity Testing,
etc.)
"Safety" Topics,
i.e., those relating
to in vitro and in
vivo pre-clinical
studies
(Carcinogenicity
Testing,
Genotoxicity
Testing, etc.)
"Efficacy" Topics,
i.e., those relating
to clinical studies
in human subject
(Dose Response
Studies, Good
Clinical Practices,
etc.)
"Multidisciplinary"
Topics, i.e., cross-
cutting Topics
which do not fit
uniquely into one
of the above
categories
(MedDRA,
ESTRI, M3, CTD,
M5)
ICH Guidelines

95. Q1A(R2) : Stability Testing of New Drug Substances and Products
Q1B : Stability Testing : Photostability Testing of New Drug
Substances and Products
Q1C : Stability Testing for New Dosage Forms
Q1D :Bracketing and Matrixing Designs for Stability Testing of
New Drug Substances and Products
Q1E : Evaluation of Stability Data
Q1F : Stability Data Package for Registration Applications in
Climatic Zones III and IV
Stability

96. Q2(R1) : New title: Validation of Analytical Procedures: Text and
Methodology
Previously: Text on Validation of Analytical
Procedures Validation of Analytical Procedures:
Methodology (in Q2(R1))
Q3A(R2) : Impurities in New Drug Substances
Q3B(R2) : Impurities in New Drug Products
Q3C(R3) : Impurities: Guideline for Residual Solvents
Analytical Validation
swaroop14/10/13 96

97. Pharmacopoeias
Q4 : Pharmacopoeias
Q4A : Pharmacopoeial Harmonisation
Quality of Biotechnological Products
Q5A(R1) : Viral Safety Evaluation of Biotechnology Products Derived from
Cell
Lines of Human or Animal Origin
Specifications
Q6A : Specifications : Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances (including Decision
Trees)
Q6B : Specifications : Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products
Good Manufacturing Practice
Q7A : Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients
Analytical Validation
swaroop14/10/13 97

98. Q8(R1) : Pharmaceutical Development
Q9 : Quality Risk Management
Q10 : Pharmaceutical Quality System
Analytical Validation
swaroop14/10/13 98

99. Efficacy guidelines
Efficacy Topics
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E6: Good Clinical Practice : Consolidated Guideline
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group and Related Issues in Clinical Trials
Efficacy Guidelines
swaroop14/10/13 99

100. M1- MedDRA : Medical Terminology
M2- ESTRI : Electronic Standards for the Transfer of Regulatory
Information
M3- (R2) : Nonclinical Safety Studies for the Conduct of Human
Clinical Trials and Marketing Authorization for
Pharmaceuticals
M4- CTD: The Common Technical Document
M5 : Data Elements and Standards for Drug Dictionaries
Multidisciplinary Guidelines
swaroop14/10/13 100

101. swaroop14/10/13 101