management of clinical trials: sponser perspective from falgun vyas

Conduct of clinical trials: an overview:

Sponsor perspective

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Outlines of the presentation

Standard Operating Procedures (SOPs) for clinical trial

Protocol – a brief overviewSelection of Clinical investigator Investigator training (during SIV and

meeting)Periodic monitoring Audits/ inspections

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SOPs for clinical trial

“Detailed, written instructions to achieve uniformity of the performance of a specific function".

Majority of penalties from regulatory authority imposed due to the carelessness which is a byproduct of not following SOPs in performing clinical trials.

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SOPs answers

- 4 Ws and H concept of clinical trial management

SOP should be prepared

with utmost care

and then it should be

followed religiously

who

what

when

where

how

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Objectives of SOPs

Standardize the working practices

Improve and maintain the quality of operations

Ensures quality, consistent and reproducible results

Defines the methodology to be followed

Defines the roles and responsibilities of the individuals

Ensures compliance to regulatory guidelines

Saves times 07:54 AM

Effective SOP should

Simple, easy to understand

Comprehensive

Differentiate between instructions and general

information

Describe procedure in a familiar way

Descriptive title07:54 AM

Protocol: definition

“A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.”

Background and rationale for study allows researchers at multiple locations to

perform the study in same way, so that their data can be combined

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Protocol: the plan; at the heart of every trial

Organizations have their own format Generated from a standard template, which

complies with regulatory requirements and company policy

‘copied and pasted’ from a previous protocol avoid repetition in multiple sections Better to have protocol review boards with

representatives from QA, data management, physician and statistician.

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Protocol

After approval of the protocol by the ethics committee and the regulatory authority, any changes must be documented.

Signed off by a senior representative of the medical department, the statistician & a medical advisor

Professional responsibility for the content Each individual investigator will sign the

protocol, thereby agreeing to comply with it07:54 AM

Protocol amendments

Minor: known as protocol revisions or administrative amendments

no impact on risks, clinical decision-making

Major: more significant inclusion/exclusion criteria, a lab test & changes

to definition of what constitutes an AE Any change must be submitted to an IRB. Some

IRBs merely acknowledge their receipt, while others actively review & approve changes

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Protocol Deviation

any change, divergence, or departure from the study design or procedures

Failure of subject to return unused study drug Participant is seen outside of the visit “window” Participant forgets to take 1 dose of study

medication

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Protocol Violation

Deviation that affect the subject's rights, safety, or well being and/or accuracy and reliability of the study data.

Failure to obtain prior informed consent/inadequate or improper consent procedure

Enrolled not meet eligibility criteria Withdrawal criteria met but not withdrawn Wrong treatment/dose Excluded concomitant medication Failure to follow protocol related to primary efficacy outcomes Loss of samples/data Repeated minor deviations A breach of confidentiality

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Minor protocol deviations- NO RISK

any change from study protocol-not been approved by the IRB and which DOES NOT have a major impact

only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of telephone number(s)).

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Reporting of protocol deviations

Protocol violation should be reported within __ days of the investigator’s knowledge of the deviation. Reports should be made using the Deviation Report Form

Protocol deviation documented in the study file; not need to be submitted to the EC as they occur-annual study status report to EC and at final study closure.

Subject-specific waiver from sponsor07:54 AM

Selection of an investigator and site pre-assessment

Objectives of Site Selection Assessment of potential problems Budget estimate Concerns about site / investigator Decision about conduct / site

Investigator = Protective Physician + Responsible Researcher

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Selection Process

Identifying Potential Investigators Marketing department Literature Review Medical society directories Reference from investigator Professional colleagues Clinical trial registries

Potential

investigators

Criteria for

evaluation

Report

Feasibility study

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Investigator Facility Protocol feasibility

Qualifications Appropriateness Availability of potential subjects

License Storage facilities Interest level

Specialty Special equipment Study coordinator availability

Clinical trial experience Active practice Attendance of investigator meeting

FDA audits EC availability Competing studies

Site evaluation

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SELECT criteria

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Knowledge & Skills for Feasibility Study

Knowledge

Disease Drug Design Protocol GCP SOPs Investigator Literature search

Skills

Business etiquette Communication Decision making Interpersonal Planning Time management Negotiation Computer

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Feasibility Study

Questionnaire Initial contact – phone / email Visit Report Discussion Decision

Selection of Site is Art Of Investigating

Investigator07:54 AM

Investigator meeting and training

sponsorreg

ulatoryvoluntee

rEthics

committee

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Difference between practice and research

Practice ≠

- exercise of an occupation or a profession– No protocol– Administer to all

patients– Some documentation– Not intended to

publish

Research

– systematic investigation designed to contribute to generalizable knowledge – Protocol– Administer to some

patients– Much documentation– Intend to publish

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Investigator training

Ethically, legally & clinically responsible for the conduct of study

PIs primary clinicians routinely claim to be busy to attend training, not be allowed to conduct

GCP training responsibility of sponsor- GCP noncompliance linked to inadequate training.

Sponsors and EC each having authority to mandate GCP training as a prerequisite

In US, holds IRBs accountable for dismal state of investigator GCP training!! 07:54 AM

Challenges with investigator training

Busy investigator Coordinators can be trained in the GCP training

several times but investigators not finding time Coordinator training is not surrogate Not understanding the importance ”what’s in it

for me”? Poor past history

Experienced investigator “oh, I know all about that.”

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Investigator meeting

Complex protocols, new technologies and increased regulatory scrutiny have all made study execution more challenging

Amount of information a site must understand about a protocol is enough to make one's head spin. Moreover, sites participating in several studies; a lot of room for error

Primary goal of meeting-- improve the performance of study site staff and ensure quality of data

Ultimate purpose of the investigator meeting: to enable the safe and effective execution of a study protocol.

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Make meetings better and more effective

Improved and simplified agendas, Increased interactivity, Shorter meetings, Less travel time, Enhanced speaker performance and An elimination of training redundancies. Start with training outcomes in mind and plan their

meetings around those stated goals. Incorporating adult learning techniques such as

interactive case studies or break out sessions07:54 AM

eLearning alternatives

Saves time and at the same time provide a self-paced and effective training

Can be used to track who has completed and, comprehended the training and allow the sponsor to retain training records thus addressing potential compliance issues

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Optimal solution: in-person meetings and eLearning

Both. i.e. experienced investigators-eLearning, while inexperienced investigators & coordinators-in person

Another option everyone’s GCP training via eLearning, & then a shorter, more focused protocol specific meeting

After training no resources to draw any output- only field monitors-this run the risk of allowing to forget much

Turnover among site (or sponsor) staff, namely ensuring that everyone receives the same training

Benefits of continuous education: higher quality data, better performing sites, enhanced site relationships, and significant cost and time savings.

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Informed consent

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Informed consent process

Investigator’s Responsibility Continuous process

– starts with initial presentation of research activity – continues until the subject participation ends

present the information accurately In a manner minimizing the possibility of

coercion or undue influence

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Methods to improve consent process

To record the consent process using recorders

Consent for recording consent QuIC-

Questionnaire to measure subjects' actual vs. perceived understanding of CT what it includes: basic elements,

therapeutic misconception,

language and structure Group discussion Giving documents well in advance

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Documentation of the Informed Consent Process:

Check all that apply The subject meets all eligibility requirements.

Discussed, explained and reviewed the consent form with subject.- add time schedule

Verbal consent/ Surrogate consent was obtained (per IRB approved consent process)

All of the subject’s questions were answered/concerns addressed. (document multiple subject question)

Subject did not have any questions/concerns

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Documentation of the Informed Consent Process:

Subject was given time to review the consent form and to discuss participation in this study with family members/others.

The subject has agreed to participate in study & signed/dated a valid consent form prior to the start of any study procedures.

The consent process was witnessed by a third party (if applicable).

Witnessed by:

A copy of the signed and dated consent form was given to the subject.

A copy of the signed and dated consent form was placed in the medical record/ research record.

Documentation of other conversation

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Monitoring of trial: Difference between QC and QA

QC

the operational techniques and activities undertaken by all; to verify that the quality requirements fulfilled

Includes checks that the data recorded are consistent with source documents; correct dose administered & SOPs and protocol are followed

QA

Verifies that the QC has satisfied these requirements.

Includes the establishment of SOPs that oblige staff to follow uniform practice, and checks that QC is in place and is effective.

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Periodic monitoring: Objectives

1) Documentation of Informed Consent Process.

2) Protocol enrollment eligibility criteria

3) Data entry is complete & consistent between CRFs and source Documents.

4) IP Accountability- accurately documented

5) Ensure Laboratory procedures documented

6) Ensure compliance of all Essential Regulatory Documents per regulations

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The intensity of monitoring

Vary across studies and among sites Who will monitor-

– sponsor’s SOPs, – the complexity of the protocol,– condition being studied, – the experience of the investigator and – the training and experience of the CRA

Overall plan remain fairly consistent,

but strategy for individual sites may change depending on study conditions and site performance

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Frequency of monitoring visits

Complexity of protocol Disease being evaluated Experience of the investigator/staff Number of study subjects enrolled at the site Rate of enrollment Site performance Sponsor monitoring SOPs CRA experience and effectiveness

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Monitoring activity

General plan for what will be monitored at each site visit

Most sponsors have a site visit or monitoring report-which is a standard document that a CRA will use for all field monitoring visits

Serves as both a checklist for the CRA and as documentation of the visit.

However, the CRA must not view this as the only list of activities that must be done.

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Top 5 deficiency categories for site inspections

1. Failure to follow the protocol

2. Failure to keep adequate and accurate records

3. Problems with the informed consent form

4. Failure to report adverse events

5. Failure to account for the disposition of study drugs

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Audits

A Systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted and the data were recorded, analysed and accurately reported according to the

- Protocol, - Sponsor’s SOP - Good Clinical Practice and - Applicable Regulatory requirement

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What is difference betweenAudit and Inspection

Audit

Inspectors of the company who work for a active clinical quality assurance (CQA) function (i.e. Sponsor/CRO)

To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements.

Inspection

Inspector by government, through the agency of the regulatory or competent Authority (i.e. FDA/DCGI)

To ensure that trial related obligations and acceptability of resultant clinical data is in support of a new drug approval.

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Monitoring

continuous process i.e. it is a part of the study,

done for each and every site and for every subject, 100% for each activity

Responsibility of the Sponsor only,

Monitoring is Quality Control

Auditing

not a continuous process, it may or may not happen

few sites and selected subjects; samples

done by Regulatory body as well as sponsor

Auditing is Quality Assurance

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What can be Audited:

Site Investigators and Study Team IRB/IEC Sponsor CRO, if involved Laboratories Pharmacy (e.g. Investigational Drug Services) Devices (e.g. ECG, Biomedical, Engineering)

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How they select site:

Study oriented audits:

– Patient Enrollment: Highest enrolling sites

– Patient Retention: Large no. of screen failures, drop-out rates

– AE: Large no. of SAE at only 1/2 sites

– Trial Importance: Pivotal studies.

Investigator oriented audits

generally occur when the drug regulatory authority has cause to suspect particular research’s conduct i.e. “For-cause Audit”

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Audit Procedure

Audit plan/Agenda Notify conduct of audit to CRA and Site present their credentials (photo ID) & a Notice

of Inspections Form Introductory Meeting start auditing by reviewing specific data interview site staff directly involved in trial

activities and process Closing meeting (exit interview)

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How to select sample no. of CRFs for SDV

square root of number of CRFs plus one (screened/randomized)

a minimum range-3-5 CRFs. 100 % SDV for ICFs and then 100 % of SDV

for 10 % of total CRFs. all primary efficacy data and AE would be

audited 100% for all patients randomized and/ or enrolled.

If particular problems found then07:54 AM

Auditor’ s common observations for study

1. Protocol Non-adherence

2. Inadequate & inaccurate records

3. Failure to report adverse events

4. Failure to report concomitant Rx

5. Inadequate drug accountability

6. IRB/IEC problems

7. Informed Consent issues

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After Audit Procedure:

After the Audit is complete, the Auditor prepare an Audit certificate Audit report / Establishment Inspection Report

(EIR):Classification Type of Letter

NAI (No Action Indicated) Notice of no significant deviations

VAI (Voluntary Action Indicated) Informational

OAI (Official Action Indicated) Warning

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Thank you any??

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