2. Outlines of the presentation
Standard Operating Procedures (SOPs)
for clinical trial
Protocol – a brief overview
Selection of Clinical investigator
Investigator training (during SIV and
meeting)
Periodic monitoring
Audits/ inspections 9:53 PM
4. 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.
9:53 PM
5. SOPs answers
- 4 Ws and H concept of clinical trial management
who SOP should be prepared
with utmost care
how what and then it should be
followed religiously
where when
9:53 PM
6. 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
9:53 PM
7. Effective SOP should
Simple, easy to understand
Comprehensive
Differentiate between instructions and general
information
Describe procedure in a familiar way
Descriptive title
9:53 PM
8. 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
9:53 PM
9. 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.
9:53 PM
10. 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 it
9:53 PM
11. 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
9:53 PM
12. 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
9:53 PM
13. 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 9:53 PM
14. 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)).
9:53 PM
15. 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 sponsor
9:53 PM
16. 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
9:53 PM
17. Selection Process
Potential Criteria for Feasibility
Report
investigators evaluation study
Identifying Potential Investigators
Marketing department
Literature Review
Medical society directories
Reference from investigator
Professional colleagues
Clinical trial registries
9:53 PM
18. Site evaluation
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
9:53 PM
20. Knowledge & Skills for Feasibility Study
Knowledge Skills
Disease Business etiquette
Drug Communication
Design Decision making
Protocol Interpersonal
GCP Planning
SOPs Time management
Investigator Negotiation
Literature search Computer
9:53 PM
21. Feasibility Study
Questionnaire
Initial contact – phone / email
Visit
Report
Discussion
Decision
Selection of Site is Art Of Investigating
Investigator
9:53 PM
23. Difference between practice and research
Practice ≠ Research
- exercise of an – systematic investigation
occupation or a designed to contribute to
profession generalizable knowledge
– No protocol – Protocol
– Administer to all – Administer to some
patients patients
– Some documentation– Much documentation
– Not intended to – Intend to publish
publish
9:53 PM
24. 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!! 9:53 PM
25. 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.” 9:53 PM
26. 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.
9:53 PM
27. 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 sessions
9:53 PM
28. 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
9:53 PM
29. 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. 9:53 PM
31. 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
9:53 PM
32. 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
9:53 PM
33. 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
9:53 PM
34. 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
9:53 PM
35. Monitoring of trial:
Difference between QC and QA
QC QA
the operational Verifies that the QC has
techniques and activities satisfied these
undertaken by all; to requirements.
verify that the quality
requirements fulfilled
Includes checks that the Includes the
data recorded are establishment of SOPs
consistent with source that oblige staff to follow
documents; correct dose uniform practice, and
administered & SOPs and checks that QC is in
protocol are followed place and is effective.
9:53 PM
36. 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
9:53 PM
37. 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
9:53 PM
38. 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
9:53 PM
39. 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.
9:53 PM
40. 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
9:53 PM
41. 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
9:53 PM
42. What is difference between
Audit and Inspection
Audit Inspection
Inspectors of the Inspector by government,
company who work for a through the agency of the
active clinical quality regulatory or competent
assurance (CQA) function Authority (i.e. FDA/DCGI)
(i.e. Sponsor/CRO)
To ensure that a site is To ensure that trial
complying with Protocol, related obligations and
SOP, GCP and acceptability of resultant
Applicable regulatory clinical data is in support
requirements. of a new drug approval.
9:53 PM
43. Monitoring Auditing
continuous process i.e. it not a continuous process,
is a part of the study, it may or may not happen
done for each and every few sites and selected
site and for every subject, subjects; samples
100% for each activity
Responsibility of the done by Regulatory body
Sponsor only, as well as sponsor
Monitoring is Quality Auditing is Quality
Control Assurance
9:53 PM
44. 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)
9:53 PM
45. How they select site:
Study oriented audits: Investigator oriented
– Patient Enrollment: audits
Highest enrolling sites generally occur when the
– Patient Retention: Large drug regulatory authority
no. of screen failures, has cause to suspect
drop-out rates particular research‟s
– AE: Large no. of SAE at conduct i.e. “For-cause
only 1/2 sites Audit”
– Trial Importance: Pivotal
studies.
9:53 PM
46. 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) 9:53 PM
47. 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 then
9:53 PM
48. 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
9:53 PM
49. 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
9:53 PM
Regulatory Authority of India generates majority of its revenue? It’s hard to believe, but it is actually through penalties. The amounts reaches INR 120 Crores every year, only from penalties.
Protocol is the key to the control of a clinical trial-allows researchers at multiple locations to perform the study in exactly the same way, so that their data can be combined as though they were all working together
-‘copied and pasted’ from a previous protocol, but care needs to be taken to avoid information specific to the previous trial suddenly appearing in the text of the new protocol.
signed off by a senior representative of the medical department sponsoring the clinical trial, the statistician involved in the preparation of the protocol and, perhaps, a medical advisor specialising in the indication or procedure.These signatories take professional responsibility for the content of the protocol
Examples of minor: correction of spelling mistakes, page renumbering, or changing the name of sponsor personnel
A protocol deviation is any change, divergence, or departure from the study design or procedures of a research protocol that is under the investigator’s control and that has not been approved by the IRB. Upon discovery, the Principal Investigator is responsible for reporting protocol deviations to the IRB using the standard reporting form.
DOES NOT have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy and reliability of the study data
Subject-specific waiver from sponsor. When a deviation occurs it should be reported to the sponsor as well as the IRB. In some instances a sponsor will issue a waiver related to a specific subject, to continue the subject in the study. These waiver letters should be submitted to the IRB along with the Deviation Report Form (if required) and also listed on the Continuing Review Deviation/Waiver Tracking Log. Examples of sponsor waivers are:it is in the subject's best medical interest to remain on studyexception to inclusion/exclusion criteria (age, concurrent medication)visits out of sequence or out of protocol "window"injection of study drug in left arm rather than right arm
Ethically, legally and clinically responsible for the conduct of the study
Special training is required.laws, regulations and guidelines for clinical research are detailed and specific.
In US, dept. health and human services holds IRBs accountable for dismal state of investigator GCP training!! Then sponsor responsible
some past experience of poorly designed, developed or delivered & consequently remember as irrelevant and waste of time.
Simply thinking about the amount of information a site must understand about a protocol—inclusion/exclusion criteria, procedures related to each visit, adverse event reporting, lab procedures, recruitment strategies—is enough to make one's head spin. The common practice to hold an investigator meeting that doctors and study coordinators are supposed to flock to in order to learn about the protocol at hand, ask questions, and otherwise prepare themselves for participation in the upcoming study
Incorporating adult learning techniques such as interactive case studies or break out sessions can be a far more effective method of training than showing hundreds of PowerPoint slides.
protocol-specific topics such as scientific background and inclusion/exclusion criteria. After training no resources to draw any output- only field monitors-this run the risk of allowing to forget muchgreater benefit in providing "continuing education" resourceAfter training no resources to draw any output- only field monitors-this practice run the risk of allowing site personnel to forget much of what was covered at the meeting, but having sponsor personnel repeatedly bogged down answering the same questions over and over again to different sites is surely not the most efficient way to do business. study execution from more of a site management or site support perspective leads one to the conclusion that there will be far greater benefit in providing some kind of "continuing education" resource that is available to all participants for the life of the studyIn addition to addressing issues of timing and sponsor resource demands, this type of approach also solves the problem that occurs when there is turnover among site (or sponsor) staff, namely ensuring that everyone receives the same training.
to record the consent process using digital recorders-can be saved to a computer hard drive or cd-particularly valuable function in high-risk studies, especially when vulnerablepopulations-adequacy of consent challenged, by a dissatisfied subject, investigators would have an easily accessible record of what transpired consent to be obtained prior to recording the consent process (verbal consent would hopefully suffice)QuIC-Quality of Informed Consent, a brief questionnaire, to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trialsIncorporates the basic elements of informed consent, assesses the therapeutic misconception, and employs the language and structure of template for informed consent documentstherapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), Transpire=occur, happened
sponsors worry-sending out consent documents in advance will scare people and discourage participationconsent forms in the hands of prospective enrollees days before they step foot in the clinic. Sponsors worry, but she believes it gives people an opportunity to highlight sections that concern or confound them and write questions in the margins so they can make a truly informed decision- subject’s comprehension improved about the study-less drop outQuestions are heavily encouraged and if comprehension is still a problem, those people simply don't get enrolledFor pediatric trials, children who express worries about blood draws or injections also don't get enrolled—no matter how enthusiastic their parentsAt every study visit, coordinators go over what to expect moving forward and remind participants of their volunteer status,Coordinators spend an hour with prospective study subjects completely reading through consent forms out loud to ensure the information gets properly digestedhighlight certain sections, such as duration of the trial and possible side effects, which tend to be decisive enrollment factorshigh-enrolling obesity trials, the site will do a "group consent" of 20 to 25 people simultaneously if the sponsoring company approves. "When one person in the room asks a question, everyone benefits,- Patients also have the opportunity to ask questions privately regarding any personal matters. Enrollees who have been group consented seem to have a somewhat better retention rate and reliably show up for study visits- sabkasathsabkawiswassponsors provide treatment allocation information after a trial ends, says Vigliotti, and not just to satisfy participants' curiosity: "It gives them the sense that they've come full circle with us...and gives us a great way to continue building and establishing rapport with them." This type of follow-up gives former volunteers a sense of connection to the clinical research enterprise
wikiIntensive in early phase I studies, the CRA may be required to be present during all or part of a subject’s treatmetCRA is the sole monitor for a site, while other times the CRA will co-monitor with other CRAs
To be successful as a CRA, it is important to develop a sense for what you should monitor at each site and how much attention should be given to each activity. It helps to be aware of where problems are most likely to arise during the conduct of a study. A good indication of potential problems is the list of activities that received the most deficiencies during U.S. Food and Drug Administration audits. This list is published annually by the Center of Drug Evaluation and Research (CDER) and has remained essentially unchanged for over a decade.
top 5 deficiency categories for site inspections (2001 report) These areas, in addition to the things the sponsor wants emphasized, should receive specific attention during monitoring visits. Sponsor expectations for studies are important. Independent CRAs and those employed by Contract research organizations need to spend enough time with sponsors’ representatives to clearly understand those expectations.
Def in (ICH-GCP Sec 1.6)
In simple terms Monitoring is Quality Control, Auditing is Quality Assurance.The objective of both these systems being ensuring the quality in the conduct of clinical trials.
different methods SDV- source data verificationhttp://www.gcphelpdesk.com/index.php/faqs/58-quality-assurance-and-auditsSome companies only allow one day for an audit for one auditor, and in this case it would be difficult to review more than three CRFs in adequate detail unless the study was very simple. Particular problems found then it might be necessary to extend the review to more CRFs, or if there are so many discrepancies on the first two CRFs that there is no point reviewing any more as the recommendation would be for someone to re-monitor all CRFs.
Audit certificate: A declaration of confirmation by the auditor that an audit has taken place.Audit report / Establishment Inspection Report (EIR): A written evaluation by the sponsor's auditor of the results of the auditVAI: Objectionable conditions were found and documented but the District and/or Center is not prepared to take or recommend any of the regulatory (advisory, administrative, or judicial) actions listed below since the objectionable conditions do not meet the threshold for regulatory action. Any corrective action is left to the establishment to take voluntarilyOAI: Objectionable conditions were found and one of the regulatory actions listed below should be recommended. Includes voluntary recalls where the district has decided conditions warrant regulatory (advisory, administrative, or judicial) action.