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Life Cycle of Clinical Trials
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Clinical Trials Flow Process: The life Cycle of Clinical
Trials
Tamer Hifnawy MD. Dr. PHAssociate Professor
Public Health & Community MedicineFaculty of Medicine – BSU- Egypt
College of Dentistry Taibah University- KSAVice 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 Clinical TrialsClinical
Development Plan
BEFORE
Development Plan
Study
Protocol
Preparation of trial
Clinical Trials Clinical Trials
BEFORE
Study
Protocol
Preparation of trial
Pre-Study Activities
Clinical Trials Clinical TrialsDevelopment Plan
BEFORE
Development Plan
Study
protocol
Preparation of trial
Pre-Study Activities
DURING
IP
Monitoring visits
BEFORE
Clinical Trials Clinical Trials
Study
Protocol
Preparation of trial
Serology+
Clintrial
CRF
AFTER
Monitoring visits
Pre-Study Activities
Clinical Trials Clinical Trials
BEFORE
Development Plan
DURING
IP
Monitoring visits
Serology
CRFData analysis
Study
Protocol
+
Development PlanPreparation of trial
Clintrial
Study report
Registration file
Scientific publications
IP
Pre-Study Activities
BEFORE
DURING
AFTEREnd of study activity
Clinical Trials Clinical Trials
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
• 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
• Sample of label(s) attached to IMP container
Before clinical phase of trial commences INV SPO
Where
required
• 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)
• 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 trialINV SPO
where
required
• 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
• 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
• 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
• IMP accountability at site
• Signature sheet
• Record of retained body fluids/tissue samples (if any)
INV SPO
During trial
• 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
• 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
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 investigator’s 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
Don’t 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
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
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
INTENSITYGrade 1 - MILDTransient events, requiring no special
treatment and not interfering with patient's daily activities
Grade 2 - MODERATEEvents 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 – SEVEREUnacceptable 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. 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
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
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 MedicineFaculty of Medicine, Beni Suef University, EgyptCollege of Dentistry Taibah University, KSACertified Trainer on Ethics of Human ResearchResearch ConsultantEmail: [email protected] [email protected] [email protected]: +201114130107 Egypt +966564356123 KSA