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: tamer.hifnawy@med.bsu.edu.eg thifnawy@taibahu.edu.sa thifnawy@yahoo.comMobile: +201114130107 Egypt +966564356123 KSA