CONGENITAL HYPERTROPHIC PYLORIC STENOSIS by Dr M.KARTHIK EMMANUEL
Clinical trials flow process
1. Clinical Trials Flow Process:
The life Cycle of Clinical Trials
Tamer Hifnawy MD. Dr. PH
Associate Professor
Public Health & Community Medicine
Faculty of Medicine – BSU- Egypt
College of Dentistry Taibah University- KSA
Vice Dean For Quality, Development & International Affairs
Certified Trainer for International Research Ethics
2. Objectives
Developing/Writing a protocol.
Developing an Investigator Site File (ISF) –
Regulatory Binder.
Screening, Recruitment, Enrollment and
Retention.
Safety reporting (SAE &AE) SUSARS.
Interim and Annual Reports.
End of Study Visit.
3.
4. The great tragedy of science.. the
slaying of a beautiful hypothesis
by an ugly fact.
Thomas Henry Huxley
10. Monitoring visits
Serology
CRF
Data analysis +
Development Plan
Preparation of trial
Study report
Registration file
Scientific publications
IP
Pre-Study
Activities
End of study activity
Clinical Trials
12. General Information
Protocol title, and date.
Name and address of the Investigator &
sponsor
Name, title, address, and telephone
number(s) of the sponsor's medical expert
for the trial.
13. Background Information
Name and description of the investigational
product(s).
A summary of findings from nonclinical
studies that potentially have clinical
significance and from clinical trials that are
relevant to the trial.
Summary of the known and potential risks
and benefits, if any, to human subjects.
Description of and justification for the route of
administration, dosage, dosage regimen, and
treatment period(s).
14. Background Information
A statement that the trial will be conducted
in compliance with the protocol, GCP and
the applicable regulatory requirement(s).
Description of the population to be studied.
References to literature and data that are
relevant to the trial, and that provide
background for the trial.
15. Trial Objectives and Purpose
A detailed description of the objectives and
the purpose of the trial.
16. Trial Design
Primary secondary endpoints, if any, to be measured
during the trial.
A description of the type/design of trial to be conducted
(e.g. double-blind, placebo-controlled, parallel design)
and a schematic diagram of trial design, procedures and
stages.
A description of the measures taken to minimize/avoid
bias, including:
(a) Randomization.
(b) Blinding.
A description of the trial treatment(s) and the dosage
and dosage regimen of the investigational product(s
17. Selection and Withdrawal of
Subjects
Subject inclusion criteria.
Subject exclusion criteria.
Subject withdrawal criteria (i.e. terminating
investigational product treatment/trial
treatment) and procedures.
18. Assessment of Efficacy
Specification of the efficacy parameters.
Methods and timing for assessing,
recording, and analysing of efficacy
parameters.
19. Assessment of Safety
Specification , methods & timing of safety
parameters.
Procedures for eliciting reports for
recording and reporting adverse event.
The type and duration of the follow-up of
subjects after adverse events.
20. Statistics
Statistical methods to be employed, and
planned interim analysis(ses).
Sample size & its justification (Power).
The level of significance to be used.
Criteria for the termination of the trial.
21. Quality Control and Quality
Assurance
Ethics
Data Handling and Record
Keeping
Financing and Insurance
22. Objectives
Developing/Writing a protocol.
Developing an Investigator Site File (ISF) –
Regulatory Binder.
Screening, Recruitment, Enrollment and
Retention.
Safety reporting (SAE &AE) SUSARS.
Interim and Annual Reports.
End of Study Visit.
Key Players in Clinical Trials
25. Sections
Grouped in 3 sections:
1) before the clinical phase of the trial commences,
2) during the clinical conduct of the trial, and
3) after completion or termination of the trial
26. • Investigator Brochure
• Signed protocol, amendments, sample CRF
• Informed consent and any other written
information given to subject
• Advertisement to recruit subjects
• Financial aspects of trial
• Insurance statement, where required
• Signed agreement between involved parties
Before clinical phase of trial
commences INV SPO
27. • Dated, documented EC favorable opinion
• EC membership list / composition
• Clinical Trial Authorization
• CVs of investigator/sub-investigators
• Laboratory normal values/ranges
• Laboratory accreditation/certification
• Sample of label(s) attached to IMP container
Before clinical phase of trial
commences INV SPO
Where
required
28. • Instructions for handling IMPs & materials
• Shipping records for IMPs & materials
• Certificate(s) of analysis for shipped IMPs
• Decoding procedures, if trial blinded
• Master randomisation list
• Pre-trial monitoring report (site suitable)
• Initiation monitoring report
Before clinical phase of trial
commences
INV SPO
(or
third party)
(or
third party)
29. • Effective commencement date to CA, EC
• IB updates
• Revisions to protocol/amendment(s), CRF,
informed consent form, other written info for
subjects, advertisements, etc.
• Dated, documented EC favorable opinion of
substantial amendments
• CA authorization of substantial amendments
During trial
INV SPO
where
required
30. • Updates of CVs, CVs for new investigators
• Updates to laboratory normal values/ranges
• Updates to lab accreditation/certification
• Documentation of IMP & materials shipments
• Certificate(s) of analysis for new batches of
IMPs
• Monitoring visit reports
INV SPO
where
required
During trial
31. • Relevant communications other than site visits
• Signed informed consent forms
• Source documents
• Signed, dated, completed CRFs
• Documentation of CRF corrections
• SAE reports (Investigator to Sponsor)
INV SPO
copy
original
copy
original
During trial
32. • Notification by sponsor to investigators of
safety information
• Interim or annual reports to EC & CA
• Subject screening log
• Subject identification code list
INV SPO
Where
required
During trial
33. • IMP accountability at site
• Signature sheet
• Record of retained body fluids/tissue
samples (if any)
INV SPO
During trial
34. • IMP accountability at site
• Documentation of IMP destruction
• Subject identification code list
• Audit certificate, if available
• Close-out monitoring report
After completion/termination of trial
INV SPO
if
destroyed at
site
35. • Treatment allocation & decoding info
• Notification(s) of end of trial to CA, EC
• Clinical study report
• Final Study Report submission to CA, EC
INV SPO
returned to
sponsor
if
applicable
After completion/termination of trial
36. Objectives
Developing/Writing a protocol.
Developing an Investigator Site File (ISF) –
Regulatory Binder.
Screening, Recruitment, Enrollment and
Retention.
Safety reporting (SAE &AE) SUSARS.
Interim and Annual Reports.
End of Study Visit.
Key Players in Clinical Trials.
37. Patient Recruitment
Determining the best way to recruit for a
particular study requires experience plus an
understanding of the recruitment process.
38. Planning
Determine who will be involved?
Discuss multiple strategies
Establish goals and timelines
Develop recruitment materials
Ads, brochures, educational materials
Plan to be flexible
39. Enrolment
Enroll only individuals who meet ALL of the
Eligibility Criteria.
Using individuals that do not meet each of the
inclusion and exclusion criteria constitutes a
protocol violation.
40. Barriers to Recruitment and Retention
Subject-related barriers
Investigator-related barriers
Protocol-related barriers
Other barriers
41. Subject Barriers
Long clinic waiting times
Inconvenient appointment scheduling
Dislike of uncertainty associated with the
trial; prefer the doctor to make the decision
about their treatment
Perceived risks outweigh benefits
Unrealistic expectations of the clinical trial
Site accessibility barriers
42. Investigator Barriers
Lack of enthusiasm for the design or aims of the
study protocol
Lack of time to recruit due to the investigator’s
clinical workload and other duties
Conflict of roles between caregiver and clinical
investigator
Investigator involved in too many clinical trials
43. Protocol Barriers
Eligibility criteria that are so tight that potential
study subjects do not qualify for entry
Protocol too difficult to follow due to complex
study designs
Lengthy study periods or excessive visit schedules
44. Other Barriers
Negative influence of the media
Social stigma associated with the research
Lengthy ethical approval process may delay recruitment and
trial commencement
Multiple studies competing for same patients
Lack of referrals from colleagues to the clinical trial
Poor choice of study site by the sponsor
Inaccurate estimate of patient population
Not enough staff resources for the site
45. Methods for Patient Retention
Don’t recruit “doubtful” patients
Determine availability to attend visits
Get as many contact details as
possible: friends, family, caregiver,
employer, usual medical practitioner
46. Methods for Patient Retention (cont.)
Transportation money
Be flexible
Dignity and respect
47. Methods for Patient Retention (cont.)
Clean and comfortable waiting area
Tea, coffee, sandwiches
Make patient feel special
48. Methods for Patient Retention (cont.)
Serious adverse events – explain and make
sure patient understand what is going on
Always encourage communication by
phone, email, letters
Home-visits
End of year party
49.
50. Objectives
Developing/Writing a protocol.
Developing an Investigator Site File (ISF) –
Regulatory Binder.
Screening, Recruitment, Enrollment and
Retention.
Safety reporting (SAE &AE) SUSARS.
Interim and Annual Reports.
End of Study Visit.
Key Players in clinical trials
51. Adverse Events
DEFINITION :
An adverse event is any undesirable/ untoward medical occurrence/
experience associated with the use of a medical product in a patient
and which does not necessarily have a causal realtionship with this
treatment.
KINDS OF AEs:
• Adverse event (AE)
• Serious adverse event (SAE)
• (Unexpected) adverse drug reaction (ADR)
• Serious adverse drug reaction (SADR)
Safety Reporting
52.
53. Adverse event (AE)
Any untoward medical occurrence in a
patient or clinical trial subject
administered a medicinal product and
which does not necessarily have a causal
relationship with this treatment
54. Adverse drug reaction (ADR)
A response to a drug which is noxious
and unintended and which occurs at
doses normally used in man for
prophylaxis, diagnosis, or therapy of
disease or for modification of
physiological function
55. Unexpected adverse reaction
(UAR)
An adverse reaction, the nature or
severity of which is not consistent with
the applicable product information
56. Serious adverse event (SAE)
Results in death
Is life-threatening
Requires hospitalisation or prolongation of
existing hospitalisation
Results in persistent or significant
disability or incapacity
Involves a congenital anomaly or birth
defect
Is medically significant !!!!!
57. Medically significant
An event may be considered a SAE
when, based upon appropriate medical
judgment, it may jeopardize the patient
or may require medical or surgical
intervention to prevent one of the
outcomes listed in the definitions for
SAEs
58. SUSAR
Suspected , Unexpected Serious,
Adverse drug Reactions associated with
the use of the study medication,
60. INTENSITY
Grade 1 - MILD
Transient events, requiring no special
treatment and not interfering with
patient's daily activities
Grade 2 - MODERATE
Events introducing some level of
inconvenience and may interfere with daily
activities, but are usually ameliorated by
simple therapeutic measures (may include
drug therapy)
61. INTENSITY
Grade 3 – SEVERE
Unacceptable or intolerable events,
significantly interrupting patient's
normal life and requiring systemic drug
therapy or other treatment
62. CAUSALITY
(relationship to study drug)
CERTAIN
A clinical event occurring in a plausible
time relationship to drug
administration, and which cannot be
explained by concurrent disease or
other drugs or chemicals.
63. PROBABLE
A clinical event, including laboratory
test abnormality, with a reasonable time
sequence to drug administration, unlikely
to be attributed to concurrent disease
or other drugs or chemicals, and which
follows a clinical plausible response on
withdrawal (dechallenge)
64. POSSIBLE
A clinical event with a reasonable time
sequence to drug administration, but
which could also be explained by
concurrent disease or other drugs or
chemicals.
Information on drug withdrawal may be
lacking or unclear
65. UNLIKELY
A clinical event with temporal
relationship to drug administration
which makes a causal relationship
improbable, and in which other drugs,
chemicals or underlying disease provide
more plausible explanations
66. UNASSESSABLE
A report suggesting an adverse drug
reaction, which cannot be judged
because information is insufficient or
contradictory and which cannot be
supplemented or verified
67. NOT RELATED
An adverse event, which is definitely
not related causally to drug
administration
68. SAE/SUSAR reporting
SAEs must be reported immediately to
the sponsor except for those SAEs that the
protocol or other document (e.g.
Investigator’s Brochure) identifies as not
needing immediate reporting
The investigator should also comply with
applicable regulatory requirement(s)
related to the reporting of unexpected
serious adverse drug reactions
69. Reporting of SAEs - Timelines
All Serious Adverse Events
(Immediate Reportable Events)
should be reported to the
Sponsor within 24 hours
after Detection of the Event.
Initial and Follow-up reports as soon as possible after
receipt of all the information
needed
As per Sponsor’s SOPs
As per regulatory requirements
Include reporting unexpected ADRs (SUSARs)
OR
70. What to report?
Subject number and initials
Description of the event
Severity
Causal relationship
Frequency
Outcome
Diagnostic tests
Treatment procedures
Medication administered
71.
72. Objectives
Developing/Writing a protocol.
Developing an Investigator Site File (ISF) –
Regulatory Binder.
Screening, Recruitment, Enrollment and
Retention.
Safety reporting (SAE &AE) SUSARS.
Interim and Annual Reports.
End of Study Visit.
Key Players in Clinical Trials.
73. Reporting in Clinical Trials
Describe the Plan
Report the Results
Confess to Problems
Interpret Objectively
74. End of Study Visit
To close down the study officially at the centre
• Visit performed once all patients have
completed the trial
• Last opportunity to resolve all outstanding
matters
• To collect all unused material
• A very last check
75. Close Out Visit is used to
Remind the investigator of his continuing
responsibilities
The investigator should:
- Inform the IRB/IEC on the end of the trial
- Archive all study documentation for approx. 15 years
77. THANK YOU
Tamer Hifnawy MD. Dr PH.
Associate Professor of Public Health & Community Medicine
Faculty of Medicine, Beni Suef University, Egypt
College of Dentistry Taibah University, KSA
Certified Trainer on Ethics of Human Research
Research Consultant
Email: tamer.hifnawy@med.bsu.edu.eg
thifnawy@taibahu.edu.sa
thifnawy@yahoo.com
Mobile: +201114130107 Egypt
+966564356123 KSA