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.
Conduct of clinical trials: an overview: Sponsor perspective 9:53 PM
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
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
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
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
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
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
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
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
Protocol amendmentsMinor: known as protocol revisions or administrative amendments no impact on risks, clinical decision-makingMajor: 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
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
Protocol Violation Deviation that affect the subjects 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
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
Reporting of protocoldeviations 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
Selection of an investigator andsite pre-assessmentObjectives 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
Selection Process Potential Criteria for Feasibility Report investigators evaluation studyIdentifying Potential Investigators Marketing department Literature Review Medical society directories Reference from investigator Professional colleagues Clinical trial registries 9:53 PM
Site evaluation Investigator Facility Protocol feasibilityQualifications Appropriateness Availability of potential subjectsLicense Storage facilities Interest levelSpecialty Special equipment Study coordinator availabilityClinical trial experience Active practice Attendance of investigator meetingFDA audits EC availability Competing studies 9:53 PM
Difference between practice and research Practice ≠ Research- exercise of an – systematic investigationoccupation or a designed to contribute toprofession 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
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
Challenges with investigatortrainingBusy 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 historyExperienced investigator “oh, I know all about that.” 9:53 PM
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 ones 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
Make meetings better and moreeffective 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
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
Optimal solution: in-personmeetings 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
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
Methods to improve consentprocess 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
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
Documentation of theInformed 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
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
Periodic monitoring: Objectives1) Documentation of Informed Consent Process.2) Protocol enrollment eligibility criteria3) Data entry is complete & consistent between CRFs and source Documents.4) IP Accountability- accurately documented5) Ensure Laboratory procedures documented6) Ensure compliance of all Essential Regulatory Documents per regulations 9:53 PM
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
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
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
Top 5 deficiency categories for siteinspections1. Failure to follow the protocol2. Failure to keep adequate and accurate records3. Problems with the informed consent form4. Failure to report adverse events5. Failure to account for the disposition of study drugs 9:53 PM
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
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
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
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
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
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
How to select sample no. of CRFs forSDV 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
Auditor’ s commonobservations for study1. Protocol Non-adherence2. Inadequate & inaccurate records3. Failure to report adverse events4. Failure to report concomitant Rx5. Inadequate drug accountability6. IRB/IEC problems7. Informed Consent issues 9:53 PM
After Audit Procedure:After the Audit is complete, the Auditor prepare an Audit certificate Audit report / Establishment Inspection Report (EIR):Classification Type of LetterNAI (No Action Indicated) Notice of no significant deviationsVAI (Voluntary Action Indicated) InformationalOAI (Official Action Indicated) Warning 9:53 PM