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
 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.
The great tragedy of science.. the
slaying of a beautiful hypothesis
by an ugly fact.
Thomas Henry Huxley
Clinical Trials
Preparation of trial

Clinical Trials
Preparation of trial

Clinical Trials
 Pre-Study
Activities

Preparation of trial

Clinical Trials

IP
 Pre-Study
Activities

Preparation of trial

Clinical Trials
Monitoring visits

CRF
+ Serology IP
 Pre-Study
Activities

Preparation of trial
Development Plan

Clinical Trials
Registration file
Scientific publications Monitoring visits

Study report
CRF
Data analysis + Serology
End of study activity IP
Designing a protocol
 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.
 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).
 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.
Trial Objectives and Purpose
A detailed description of the objectives and
the purpose of the trial.
 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
 Selection and Withdrawal of
Subjects
Subject inclusion criteria.
Subject exclusion criteria.
Subject withdrawal criteria (i.e. terminating
investigational product treatment/trial
treatment) and procedures.
 Assessment of Efficacy
Specification of the efficacy parameters.
Methods and timing for assessing,
recording, and analysing of efficacy
parameters.
 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.
 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.
Quality Control and Quality
Assurance

Ethics

Data Handling and Record

Keeping

Financing and Insurance

 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
Investigator Study File &
Essential Documents
 Definition
Essential Documents:

Documents which individually and

collectively permit evaluation of the conduct
of a study and the quality of the data
produced
 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
 Before clinical phase of trial
commences INV SPO

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

Dated, documented EC favorable opinion

EC membership list / composition

Clinical Trial Authorization

CVs of investigator/sub-investigators

Laboratory normal values/ranges

Laboratory accreditation/certification Where
required

Sample of label(s) attached to IMP container

 Before clinical phase of trial
commences
INV SPO

Instructions for handling IMPs & materials

Shipping records for IMPs & materials (or

third party)

Certificate(s) of analysis for shipped IMPs

Decoding procedures, if trial blinded
Master randomisation list (or
third party)

Pre-trial monitoring report (site suitable)

Initiation monitoring report
 During trial
INV SPO

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
where
CA authorization of substantial amendments required
 During trial
INV SPO

Updates of CVs, CVs for new investigators

Updates to laboratory normal values/ranges
Updates to lab accreditation/certification
where
required

Documentation of IMP & materials shipments

Certificate(s) of analysis for new batches of
IMPs
Monitoring visit reports
 During trial
INV SPO
Relevant communications other than site visits
Signed informed consent forms
Source documents
Signed, dated, completed CRFs
copy original

Documentation of CRF corrections

copy original

SAE reports (Investigator to Sponsor)

 During trial
INV SPO

Notification by sponsor to investigators of

safety information

Interim or annual reports to EC & CA

Subject screening log
Where
required

Subject identification code list

 During trial
INV SPO

IMP accountability at site

Signature sheet

Record of retained body fluids/tissue

samples (if any)
After completion/termination of trial
INV SPO
IMP accountability at site
Documentation of IMP destruction if
destroyed at
site

Subject identification code list

Audit certificate, if available
Close-out monitoring report
 After completion/termination of trial

INV SPO

Treatment allocation & decoding info

returned to
sponsor

Notification(s) of end of trial to CA, EC

Clinical study report if
applicable

Final Study Report submission to CA, EC

 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.
 Patient Recruitment

Determining the best way to recruit for a

particular study requires experience plus an
understanding of the recruitment process.
 Planning

Determine who will be involved?

Discuss multiple strategies

Establish goals and timelines

Develop recruitment materials

Ads, brochures, educational materials

Plan to be flexible
 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.
Barriers to Recruitment and Retention

Subject-related barriers

Investigator-related barriers

Protocol-related barriers

Other barriers
 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
 Investigator Barriers

Lack of enthusiasm for the design or aims of the

study protocol

Lack of time to recruit due to the investigators

clinical workload and other duties

Conflict of roles between caregiver and clinical

investigator

Investigator involved in too many clinical trials

 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
 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
Methods for Patient Retention

Dont recruit doubtful patients

Determine availability to attend visits
Get as many contact details as
possible: friends, family, caregiver,
employer, usual medical practitioner
 Methods for Patient Retention (cont.)

Transportation money
Be flexible

Dignity and respect

Methods for Patient Retention (cont.)

Clean and comfortable waiting area

Tea, coffee, sandwiches
Make patient feel special
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
 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
 Safety Reporting
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)

 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
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
 Unexpected adverse reaction
(UAR)
An adverse reaction, the nature or
severity of which is not consistent with
the applicable product information
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 !!!!!
 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
 SUSAR
Suspected , Unexpected Serious,
Adverse drug Reactions associated with
the use of the study medication,
 AE/SAE evaluation
INTENSITY
CAUSALITY
 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)
 INTENSITY
Grade 3 SEVERE
Unacceptable or intolerable events,
significantly interrupting patient's
normal life and requiring systemic drug
therapy or other treatment
 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.
 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)
 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
 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
 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
 NOT RELATED
An adverse event, which is definitely
not related causally to drug
administration
 SAE/SUSAR reporting
SAEs must be reported immediately to
the sponsor except for those SAEs that the
protocol or other document (e.g.
Investigators 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
 Reporting of SAEs - Timelines
All Serious Adverse Events should be reported to the
(Immediate Reportable Events) Sponsor within 24 hours
after Detection of the Event.

Initial and Follow-up reports as soon as possible after

receipt of all the information
OR needed

As per Sponsors SOPs

As per regulatory requirements
Include reporting unexpected ADRs (SUSARs)
 What to report?
Subject number and initials
Description of the event
Severity
Causal relationship
Frequency
Outcome
Diagnostic tests
Treatment procedures
Medication administered
 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.
Reporting in Clinical Trials
Describe the Plan
Report the Results
Confess to Problems
Interpret Objectively
 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
 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
Did we BRIDGE THE GAP?
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