Life Cycle of Clinical Trials

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.

4. The great tragedy of science.. the
slaying of a beautiful hypothesis
by an ugly fact.
Thomas Henry Huxley

5. Clinical Trials

6. Preparation of trial
Clinical Trials

7. Preparation of trial
Clinical Trials

8. Preparation of trial
Pre-Study
Activities
IP
Clinical Trials

9. Preparation of trial
Serology
+
CRF
Monitoring visits
Pre-Study
Activities
Clinical Trials
IP

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

11. Designing a protocol

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

23. Investigator Study File &
Essential Documents

24. Definition
Essential Documents:
Documents which individually and
collectively permit evaluation of the conduct
of a study and the quality of the data
produced

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

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

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,

59. AE/SAE evaluation
 INTENSITY
 CAUSALITY

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

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

76. Did we “BRIDGE THE GAP”?

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