Presentation on theme: "Orientation for New Clinical Research PERSONNEL Module 2"— Presentation transcript:
1Orientation for New Clinical Research PERSONNEL Module 2 Welcome and introductions – thanks to contributors to presentationBathroomsPresented byNC TraCS InstituteUNC Office of Clinical TrialsUNC Network of Clinical Research Professionals
2Overall Agenda for Orientation Module 1: September 12, Introduction to Clinical Research, Education, and IRBModule 2: September 19, Study Implementation, Documentation, and GCPsModule 3: September 26, Contracting and Hospital Administrative ElementsModule 4: October 3, Clinical Trial Management, Budgeting, Hospital and Research AccountingDiscuss that this Orientation Program has been divided into 4 separate days, consequtive Wednesdays, from 1-3pm. Review each of the weekly modules.Encourage attendees to attend all modules as most talks will offer something for everyone (always something to learn), but can skip some days if the topics don’t seem relevant to their research.
3Overall Agenda for Orientation Module 1: Introduction to Clinical Research, Education, and IRBModule 2: Study Implementation, Documentation, and GCPsModule 3: Contracting, COI, and Hospital Administrative ElementsModule 4: Clinical Trial Management, Budgeting, Hospital and Research AccountingDiscuss that this Orientation Program has been divided into 4 separate days, consecutive Wednesdays, from 1-3pm. Review each of the weekly modules.Encourage attendees to attend all modules as most talks will offer something for everyone (always something to learn), but can skip some days if the topics don’t seem relevant to their research.
4Study Team Responsibilities Michelle Duclos, NCRP
5Principal Investigator Ultimate administrative and fiscal responsibility for the team performance of the study subject to IRB/Institution review and oversight:The scienceThe integrityThe business operationsUnderstanding and following the protocol as approved by the IRB is the first and most critical obligation of the investigator in human subjects research
6Legal Commitments in Drug & Device Research When PI signs FDA form 1572 (for IND studies - Drugs) or "Statement of the Investigator” (for IDE studies - Devices), signing a legally binding document committing themselves to conduct study according to protocol and FDA regulations.Form 1572 is a written agreement (signed) between PI and federal government.PI’s nine responsibilities (or commitments) as stated in FDA regulations are detailed on Form 1572 for Drug Trials.While these slides specifically pertain to the 1572, if you are performing research that does not fall under the FDA jursidiction but under the HHS/OHRP the investigator has similar responsibility for the overall conduct of the protocol.
7Form FDA 1572 (excerpts)I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjectsI agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are metI agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFRI have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
8Form FDA 1572 – Oversight of Staff I agree to personally conduct or supervise the described investigation(s).I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.Common practice for PI to delegate certain study-related tasks to co-investigators and study staff.When tasks are delegated by PI, the investigator is still responsible for providing adequate supervision of those to whom tasks are delegated.PI is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the study.PI Cannot Delegate:responsibility of providing oversight and supervision of the clinical studyResponsibility for assessing causality of adverse eventsInvestigators who conduct clinical investigations of medical devices commit themselves to supervise all testing of the device involving human subjects
9Should Sub-investigator be listed in Section #6 of FDA 1572? FDA’s regulation at 21 CFR 312.3(b) states “In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Sub-investigator” includes ANY other individual member of the team.Purpose of Section #6 is to capture information about individuals who will assist the investigator and make a direct and significant contribution to the data.See Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBS – FAQs – Statement of Investigator (Form FDA 1572)Recognize the PI can’t do the whole study himself, right? It is acceptable to delegate, it is assumed this will have to happen. But, any insight on how to delegate and still supervise? Delegate appropriately to adequately trained staff, have involvement in the ongoing conduct of the study
10Should coordinator be listed on FDA 1572? The decision about whether to list a pharmacist or research coordinator on the 1572 is a matter of judgment, dependent upon the contribution that the individual makes to the study.A research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution. Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a subinvestigator in Section #6, but he/she should be listed in the investigator’s study records.A research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.Excerpt from FDA Guidance document #33
11Investigator Obligation at UNC-CH With or Without FDA Involvement Obtain IRB approval before performing the protocol and before performing any changes or additions from what the IRB has approved for the project.Perform the protocol AS APPROVED by the IRBProvide the IRB with accurate and complete information and updates as the information changesNotify the IRB of all unanticipated or serious adverse events involving risk to human subjectsProvide all reports required by the IRB on the timeline required by the IRB
12Clinical Research Coordinator (CRC) What is your title? Social/Clinical Research AssistantSocial/Clinical Research AssociateSocial/Clinical Research SpecialistResearch NurseClinical NurseProject ManagerResearch InstructorOthers?
13Primary Responsibility Per UNC OCT, role of the CRC is to “. . . ensure smooth, accurate progress of the project from the planning stage through study end (and often beyond) by acting as liaison to the investigator, the subject, the institution, and the company or government sponsor1.”Role has evolved over the years as the clinical research industry has evolvedThe specific activities delegated to the Research Coordinator by the investigator varies according to the needs of the particular study, but for all trials , the delegation of activities should be discussed well before enrollment of subjects begins and a plan for regular communication and review of activities should be in place.Skill set typically required for research coordinators –Attention to detailGood Communication SkillsFlexibilityAbility to work independentlyOrganizational skills
14Shared Responsibilities Many PI responsibilities are delegated and become the CRC’s operational responsibility Know what responsibilities belong only to PI and what roles you are capable of performing FDA Guidance Document: Investigator Responsibilities – protecting the rights, safety, and welfare of study subjectsRecommend reviewing and understanding the Guidance for Industry – investigator responsibilities – protecting the rights, safety, and welfare of study subjects.
15FDA Final GuidanceGuidance provides an overview of the responsibilities of a person who conducts a clinical investigation of a drug, biological product, or medical device (an investigator as defined in 21 CFR 312.3(b) and 21 CFR (i))Guidance and information sheets represent the Agency’s current guidance and EXPECTATIONS on good clinical practice and conduct of clinical trials.Goal of this guidance is to help investigators better meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations.Guidance intended to clarify for investigators and sponsors FDAs expectation concerning the investigator’s responsibility.To supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator or other third parties, andTo protect the rights, safety, and welfare of study subjects
16General CRC Responsibilities Protocol Evaluation Subject availabilityPersonnel requirementEquipment & facility availabilityDevelop timelinesPropose & negotiate alternatives to improve implementationThe CRC mayReview the new protocols to evaluate the feasibility of conducting the study at the site (for industry sponsor studies)Development of a study budgetPrepare
17General Responsibilities Administrative Interact with IRB, lab staff, clinic staff, pharmacy, nursing homes, assist living, churches, community centers, etcPrepare IRB documents including ICFPrepare Study BudgetAssure all documentation is maintainedInteract with SponsorInteract with PIs and sub-investigatorsCoordinate and participate in monitoring visits with sponsorComplete CRFs and submit to sponsorResolve data queriesFacilitate inspections/auditsDocument study progress
18General CRC Responsibilities Study Subjects Recruit study subjectsAssess subjects for eligibilityDiscuss study with subjectObtain informed consentSchedule subject visits/assessmentsAssure all study tests and visits are done at appropriate time intervalsFinal sign off of subject eligibility should be determined by a medical qualified staff member of the team –It is highly recommended for those study with the potential to be monitored by the FDA, that a medically qualified team member is available for questions during the consent process.
19General CRC Responsibilities Study Subjects Evaluate study subjects at appropriate intervalsAssess laboratory data and clinical signs for potential adverse eventsAdverse Events (AEs)Assist PI with gathering information to help PI determine classification, and causalityObserve and document AEsAct on PI’s recommendationMaintain follow-up until reconciliationCommunication with sponsorUltimately though it is the PI or medically qualified sub-I, that will determine the classification and causality of an adverse event. PI and sub-I should have investigator brochure available to help determine if need be.
20General CRC Responsibilities Study Subjects Provide information for treatment and reactionsAdminister or dispense investigational agent, as outlined in the protocol, under the investigator’s supervisionInvestigational Drug AccountabilityOrder, store, dispense, retrieve, logRandomization codesUnblinding proceduresPromote subject compliance by providing patient support and educationPrepare lab specimens; ship biological samples and radiologic filmsArrange for study subject compensationComply with FDA regulations for conducting clinical trials
23Protocol Implementation Research Site – Study start up meeting, documentation of training of all individuals listed on delegation logNotification to providers, nurses, clinic staff, and other team members of upcoming research protocolPre-identification of potential subjects –Once IRB approval received, contacting potential subjects regarding participation in research protocolDevelopment of a recruitment planOrganization of study materialsCreation of source documents
24Protocol Implementation Organization of study materialsRegulatory binderIRB binderCorrespondence binderProtocol binderInvestigator brochure binderIVRS informationSupply Order formsInvestigational DrugStudy Manual
25Is this how your office looks? Patient Research ChartsIf you conduct clinical research your office may look like this – especially for large industry sponsor or NIH protocols. For smaller studies and many of the studies conducted in social or behavioral research you may have only one binder per project or a regulatory binder and 1 subject binder.
26Protocol Implementation Creation of source documentsHelpful hints:review your study visit schedulereview the Case Report Forms or eCRFs to ensure you collect all information that will be documented on CRFDevelop standard forms for department that can be used across studies.ExamplesPhysical Exam formMedical history formGeneral Research Record or SOAP noteDocumentation of Informed Consent TemplateTemplates available on TraCS or OCT website – Marie will talk about next
27Depending on study development of a study start up checklist may be helpful Include reasons why we use this:Keep track of matrixs for length of study start up – to improve internal processesIncreases communication of all team membersOrganization of task needed, when managing multiple protocols
28RecruitmentA recruitment plan should be developed as soon as you have begun work on the protocol, whether investigator initiated, industry sponsored, or NIH (IRB approval of all recruitment materials is required)Advertising campaignTV, Radio, Print, WebsiteDear Doctor Letters –fax or local providers, recommend follow-up with a meeting if you want practice to helpDirect to Patient from databasesPosters, Pamphlets, Mailings (letters, post cards)Determine if Carolina Data Warehouse can be utilizedDevelop a phone screen/script as necessary for phone callsSocial networking opportunitiesCommunity events (fairs, flea markets, senior centers)Develop a UNC massCommunicate internally with departmental doctors for referrals, develop a system in department for identification of potential subjectsCommunicate with NC TraCSTalk about cost of varies recruitment campaignsTalk about whether pharma company offerring central campaign – pros and cons - you still need to have a plan at your siteTalk about our internal system to give an example
29Good Clinical Practices & Study Documentation Marie Rape, RN, BSNNC TraCS InstituteDocumentation in your study files and end with the informed consent process
30Good Clinical Practice GCP defined as “…international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.”E6 Good Clinical Practice: Consolidated GuidanceLets start with the GCP (or good clinical practice).Most clinical investigators are familiar with the term Good Clinical Practice (GCP), although their interpretation of its meaning andapplicability vary enormously. GCP has traditionally been a general term used by United States (US) government agencies, industry, and clinical researchers to describe the collection of related regulations and guidelines that, when combined, define the clinical study-related responsibilities of sponsors, investigators, monitors, institutional review boards, and others involved in the clinical research process.This is a term used synonymously with quality documentation.Has anyone heard of GCP or this guidance document??
31E6 Good Clinical Practice: Consolidated Guidance 1996: In an attempt to provide consistency among clinical trials, US, European Union, and Japan established a unified standard, called the International Conference on Harmonisation’s “Good Clinical Practice: Consolidated Guideline,” (ICH-GCP).Objective of “guidance is to provide a unified standard to facilitate mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.”E6 Good Clinical Practice: Consolidated Guidance recognized by industry sponsors as the gold standard for conduct of ethically and scientifically sound human subject research.From the Introduction of Guidance for Industry, E6 Good Clinical PracticeSeveral countries adopted ICH GCP as law, but US FDA adopted only as guidance; but as with any FDA guidance, compliance considered part of good clinical practice. Requirement to follow for industry sponsored / FDA research.What is this ICH GCP guidance document? Ever heard of it? Show Copy
32Topics Covered in ICH GCP Describes:Qualification of an investigatorEducation and training of study staffDelegation of study-related tasksRequirement for IRB reviewCompliance with the protocolResponsibility for investigational product accountabilityInformed consentSafety reportingTrial management & record keepingData quality and integrity, quality controlEssential documents for a trialShow actual document. Encourage to keep bookmarked on computer or copy at desk as reference.Document describes a lot of key topics central to conducting a quality trial. The ones we will focus on in the rest of this talk have to do with maintaining appropriate study documentation and research files (see page 21).
33Why is Adherence to GCP Important? Main tenets of GCP: research involves good science, is verifiable, monitored, well-documented, and study complies with the highest ethical standards.Adherence to GCPs:Protect the rights and well-being of human subjectsEnsure accuracy and credibility of the data and reported resultsEnsure conduct of the trial is in compliance with:the protocol/amendment(s) currently approved by the IRBapplicable regulatory requirementsinstitutional policiesall applicable rules and regulationsAdherence to GCPs will ensure the rights and well being of human subjects are protected. Also, ensure quality of the research data collected and ensure complete and verifiable for submission to FDA (and eventual approval of drug/device).
34Who Should Adhere to GCP? The general concept of GCP is essential for any research study involving human subjects.Whether conducting research involving a new drug or device, a behavioral intervention, or an interview/survey, Good Clinical Practice (GCP) provides investigators and study teams with the tools to protect human subjects and collect quality data.Following the ICH-GCP is one of the best ways to substantiate the quality of any research study and its resulting data.You might be thinking, “I’m not doing an FDA study so GCPs don’t apply to me.” While the ICH-GCP may not be a requirement, it represents the current thinking on good clinical practice in research for all kinds of studies – social behavioral as well as biomedical. A research team that actively follows the principles of GCP provides evidence of the quality of the conduct of their study and the ensuing results.
35DocumentationOnce a scientifically valid research idea has been proposed and approved, the key to successful implementation of the study lies in the documentation.“If you didn’t document it, it didn’t happen.”Validity of research data rests in the documentationResources, such as checklists and templates assist investigators & study staff in implementing, and documenting that they followed GCP and the protocol.We will go over some basic concepts about documentation and provide you with ways you can improve your research documentation.It should not be difficult for investigators and their study teams to follow GCP – it is simply a question of writing down procedures, documenting what is being done, and preparing for inspection (or at least, conducting the study as though if preparing for an inspection).
36FDA Regulations Require Investigator to Maintain Study Files For FDA Drug studies (21 CFR )prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the (drug) investigation on each individual administered the investigational drug or employed as a control in the investigationcase histories include the case report forms and supporting data (source documents).For FDA Device Studies (21 CFR )Maintain accurate, complete, and current records relating to participation in (device) investigationFDA needs a trail for the trial – complete records that support what happened to subjects in study.FDA reiterates what GCP guidance describes about maintaining study files or study documentation. Need to maintain adequate and accurate case histories or records of the subjects participation in the study. But, these concepts relevant to any research study so that everyone can follow what happened in the study.
37Source DocumentsSource Documents: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.International Conference on Harmonization E6The first place something is recorded is considered the source document for that clinical trial activityA “trail for the trial”: Source documents should create a “trail” so that anyone can verify and follow what happened throughout a clinical trial and where the data came from (an audit trail)Start with some definitions. What is a source document? Anyone??Trail for the trial commonly used statement. Others in your study team or those that come after you, must be able to understand what happened with a subject or re-create what happened in the trial. You never know when you might not be here tomorrow.
38Types of Source Documents Medical historyHospital recordsClinic & office chartsProgress notesLab notesMemorandaMeeting minutesNotes to filePhone recordsSubject diariesQuestionnairesSubject files or recordsDrug dispensing recordsRecorded data from automated instruments (DynaMap, ECG, EEG, )X-rays, scans, MRIsExamples of source documents to support researchExamples of supporting data: consent form, progress notes of MD, nurse notesSource documents are part of the supporting dataEssential that there be consistency across the records
39Example of a source document? SubjectABC3/1/06Is this an example of a source document? Yes, first place data recorded. Important to keep source documents that detail study related data that is collected.
40Case Report Forms (CRFs) CRFs are paper or electronic documents/forms designed to record all information required by the study protocol for a participant (provided by Sponsors).All information entered on CRF must be supported by source documentsIf data recorded directly on CRF, there should be an entry in subject's medical record or subject file that records date information was obtained, how and by whom.CRFs may be used as a source document IF data elements are newly created and not transcribed from other sources.FDA opinion that copies of CRF used as a source document are not a replacement for original source documentation.Most of you have also heard the terminology CRFs which is often confused with source documents. These are different from source documents in that they take all the data required of a study that has been collected on source documents and compile it on one form, the CRF. CRFs are usually provided by the sponsor, designed to record info about a subject required in a trial. They lay out visit by visit what is expected by the protocol to be collected. If investigator initiated study, you may have to design your own – specific to study data needed to analyze the research. Also very helpful as they guide you through each visit.All information entered on CRF must be supported by source documents.
41Important Events to Document The Consent Process (more than just signed consent form)Documentation of subject eligibility (inclusion/exclusion criteria)Study randomization, study drug adherence or non-adherenceCompletion of all protocol-required tests, proceduresMissed visits, subject contacts, procedures, or examinationsProtocol deviations & violations (notifications to IRB / sponsor and corrective actions)All subject contact – either via phone or in person (include date/time and reason for contact)Unanticipated problems or adverse effects and relationship to study intervention, severity, action taken and reporting to IRBSubject termination (withdraw of consent, lost to follow up, PI removal)What are some important events to document well in research files (source documents)?Protocol deviations or violations are anything that was done that did not follow the protocol as approved by the IRB. If the subject is to have visits every 2 wks while on drug and they miss a visit, it is a protocol deviation. The PI might think it is okay and subject is safe, unharmed, but it is still reportable to the IRB and the sponsor.
42Templates Improve Source Documentation Some research data collected on Hospital based forms as part of medical care:Vital signs on clinic record sheetMedication administration on MAR for inpatients,Laboratory testsHistory and physical examOther research data only collected by study staff and not maintained in Medical Record or on any other form.Use of templates to document research data helps study team collect required data and have a place to record it.Other data can be written on progress notes.So, how do you make it easier to record all those important events during a study. Use of templates will make it easier for you to collect the right information needed in a study and have a place to document exceptions to what should occur in a study. Examples of Templates to improve source documentation
43Example from UNC NCRP of a generic template to use to document the consent process or you can just write a narrative note. This can be a useful way to remind yourself what you need to do with your subject when going through the consent process. It serves as a reminder to you and also a way to improve your documentation and ensure that you have done all the right things. This isn’t something the subject signs.
44I / E Criteria Checklists Good practice for study teams to incorporate an eligibility checklist into each subject’s study record so that study staff can document on a form how each of the inclusion and exclusion criteria have been met.Create a template that is study specific, listing all the inclusion and exclusion criteria for the study and check off that subject meets each and every criteriaDocumentation of Eligibility Important!Keep supporting documentation that demonstrates that subject meets criteria (e.g., colonoscopy results to demonstrate normal colon)
45Sample Inclusion/Exclusion Criteria Checklist All Inclusions should be written to answer “yes” and All Exclusions should be written to answer “no” to avoid confusion.
46Signature by PI that Subject is Eligible If the responses to all the inclusion criteria are YES and all the exclusion criteria are NO, the subject is eligible to participate in the trial. Is the subject eligible to participate in the trial? YES NO If NO, discontinue the subject and complete the study termination form. If YES, I have reviewed the inclusion and exclusion criteria and have determined that the subject is eligible for participation in the trial. Investigator ___________________________ Date ___________If the responses to all inclusion criteria are YES and all the exclusion criteria are NO, the subject is eligible. End with a line that is signed by the investigator with a statement that he has reviewed the I/E criteria and has determined that the subject is eligible to participate in the trial. Shows involvement of PI and his agreement that subject met criteria
47Eligibility CriteriaIRB approval of protocol includes approval of inclusion & exclusion criteria as written. These eligibility criteria are NOT guidelines, but are requirements that must be followed.The “inclusion/exclusion criteria” define the study population, and ensure the safety and the integrity of the dataInvestigator may wish to enroll a subject who does not precisely fit the eligibility criteriaPI must obtain IRB approval for the change in eligibility criteriaMay make an exception for a single subject (not change criteria in protocol)After the amendment or exception is approved by IRB, the subject can be then be enrolledEnrolling subjects who do NOT meet the eligibility criteria, even if only by a small margin, potentially puts subjects at risk and is a violation of federal research regulationsEnrolling someone who does not precisely fit eligibility, even for just one subject - subject is slightly outside the age range, the lab values are slightly out of range, etc.Can’t just document that the PI determined made an exception that subject can be enrolled despite not meeting one of the eligibility criteria.
48Enrollment Note Template Study IRB #: Principal Investigator:Subject Name: ___________________ ID#: ___________Yes No1. Subject has met inclusion criteria.2. Subject has no exclusion criteria.3. Informed consent was obtained prior to any study procedures being performed.4. Subject was provided with an explanation of study procedures, risks, benefits, and alternatives, was given the opportunity to ask questions, and agrees to participate.5. Subject was given a copy of the signed consent form.6. Contact information of research staff given to subject.7. Other:Additional information:Another example, but without all the I/E criteria listed. Allows Investigator to demonstrated involvement in determining eligibility. By signing this type of note, he is stating that he has evaluated the subject and their hx and determined that they met the Inclusion Criteria and none of the exclusion criteria. Also, documents that consent obtained before any study procedures performed.Investigator’s Signature ____________________ Date ________
49Note to File TemplateA template you can use to document events or other things that don’t fit on CRFs or source documents (describes what happened and what you did). Signed by person describing situation. This is often good for a missed visit – describing the reason for the missed visit (subject called because he had a flat tire on way to appt. Appt rescheduled for next Tues because subject unable to get off work again this week).From Office of Clinical Trials
50Template for Progress Notes or PE IRB #Study Title:Subject ID#:_________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________This can be a good place for a note from you or the PI about a subject’s study visit. It could include a limited physical exam. Some study teams actually prepare a template of what their study doctor needs to exam as part of the PE (head, neck, chest) specific to that protocol. Could also be used to describe an adverse event that occurred.Signature______________ Date __________
51Telephone Contact Log Study ID __________ Subject ID __________ Date/TimeIncoming/OutgoingMessage/ConversationCommentIncomingMessageAll subject contact – either via phone or in person (include date/time and reason for contact) should be documented. Example: at 5pm, called subject to tell him his CBC was low and that he needed to come in for a repeat lab test and to reduce his dose of study medication.
52Helpful Hints for Source Documentation Mistakes and mishaps occur, visits, contacts and tests may be missed, subject might not tell you about an adverse event or problem until much laterDescribe in source documents when you learn of study-relevant information and actions taken when you became aware of information. This demonstrates due diligence.Lost to follow-up subjects:Often begins as a missed subject visit or contact. Document missed visits and actions /attempts to follow up.Document final action taken - certified letter, receipt as signed or undeliverable, notice to sponsor and IRB that no further contact will be attempted, record closedFollowing due diligence means you document what you do when you learn of study relevant information – so if subject was in car accident 3 wks ago and was hospitalized, but you didn’t find out until he came in for f/u appt, you should document this information and the date you became aware of the event (reportable SAE)
53ALCOA* for Data Quality Attributable: is it obvious who wrote it?Legible: can it be read?Contemporaneous: is the information current and in the correct time frame?Original: is it a copy; has it been altered?Accurate: are conflicting data recorded elsewhere?*Stan W. Woolen, 1999 DIA MeetingALCOA is a term used to describe data quality of study documentation. If have poor data quality, you will have poor results from your study.
54Maintaining Regulatory Files Essential Documents for conduct of Clinical Trial should be maintained together in a Regulatory BinderPurpose of Regulatory Binder:Organize essential documentsAllows research team to reference informationAllows easy access to documents by monitor, auditor, IRB, FDA, OHRPPrincipal Investigator ultimately responsible for maintenance of Regulatory Files, but task often delegated to other member of research teamOne component of the study files is the Regulatory Binder. Essential Documents outlined in GCP document.
55Regulatory Binder (Essential Documents) Signature logs (DOA and monitoring log)Screening/enrollment logsProtocol and amendmentsInvestigator’s BrochureSponsor correspondenceTraining1572, Conflict of Interest, CV’s, Licenses, Financial DisclosuresIRB membership, FWAIRB approvals and correspondenceAE log, SAEsIND Safety ReportsLocal Laboratory CLIA/CAP, normal values, Lab Dir. CVTemperature LogsSubject ID Code ListEssential Documents is another term used to refer to the contents of a Regulatory BinderKey is to maintain these documents in neat, orderly manner that would allow anyone to easily find a required document. Dividers and tabs in the binder make it much easier to navigate. Can be one large binder with everything in it, or information/documents can be subdivided like Michelle described - Regulatory binderIRB binderCorrespondence binderProtocol binderInvestigator brochure binder
56Delegation of Responsibility Log Note: The PI is ultimately responsible for all aspects of the study.Study IRB#:_____________________Study Title:_________________________________________________________________________________________________Principal Investigator: ____________________________Coordinator: _____________________*Record staff responsibilities using the following codes, list all that apply:A) Subject Recruitment E) Administers Study Medications I) Packs/ships samplesB) Obtains Informed Consent F) Drug, Biologic, or Device Accountability J) Other: ___________________C) Performs Study Assessments G) Data Management K) Other: ___________________D) Assesses Subject for Adverse Events H) Regulatory Reporting/Paperwork/MaintenanceStudy PersonnelPrinted NameTitleStudy Personnel Role(e.g. PI, Investigator, Coordinator, Pharmacist, etc.)Responsibilities*(List all letters that apply)Signature ofInitials of Study PersonnelObligationPI Signature & Date(To acknowledge roles & responsibilities)IRB ApprovedStart DateEnd Date
57Monitoring LogShould document when monitoring is performed and what was monitored.From Office of Clinical Trials
58Screening and Enrollment Log Patient NameTelephone Pre-Screen DatePotentially Eligible ?Screenin g Visit DateStudy ID NumberConsented/ Enrolled ?Eligibility *Staff InitialsYesNoYes No Screen Failure, Reason:Date: EligibleYes NoAnother document that you can keep in your study files to document subjects you screen who either are enrolled (met eligibility) or who don’t and the reason for their screen failure (something that is often neglected in the documentation but is necessary to close the loop on a subject’s participation). It also helps you to keep track of who you already screened so that you (or a future co-worker) don’t inadvertently re-screen someone who shouldn’t be in your study.
59Protocol Deviation Log Another template/form that can be used to document protocol deviations, if you don’t have one provided by your sponsor.From
60Adverse Event Tracking Log Principal Investigator:HRC Protocol #:Study Title:#Subject IDDate of EventDate PI AwareDescriptionof EventSeriousNon-seriousExpectedUnexpectedSeverity Scale (CTCAE)RelatednessDate Reported to IRB, if applicableDate of IRB ReviewOther12345678910111213141516Often times an industry sponsor will provide a similar log, but if they don’t or you are doing an investigator initiated study, you can use a template like this one.
61Documentation of AEs and UPs Keep log of AEs, SAEs, Unanticipated ProblemsTrack adverse events from time consent is signed, until resolution of any serious events - even after the study period ends.Be consistent with terminology and descriptions.Use a severity scale in evaluating adverse events (CTCAE scale or mild, moderate, severe scale) and document according to scaleDecisions regarding AE reporting and management are the responsibility of the PI so keep them in the loop and encourage documentation.The PI has the final decision on causality, severity and relationship of adverse events
62Templates Available for Documentation (NCRP or NC TraCS) Delegation of Authority (Responsibility) LogProtocol Modification TrackingAdverse Event (UP) TrackingProtocol Violation LogMemo to FileProgress Note TemplateScreening and Enrollment LogTelephone LogInvestigational Drug or Device AccountabilityConsent Process Documentation
63Informed consent process Claudia Christy, NCRP & NC TraCS Institute
64Informed Consent Process Both a DOCUMENT and a PROCESS
65Objectives Review regulatory requirements for Informed Consent Review the Informed Consent ProcessReview documentation of the Informed Consent ProcessReview additional required forms for the Informed Consent Process
66History Historical Nuremberg Code 1947 Declaration of Helsinki 1964Belmont Report 1979Code of Federal Regulations (21CFR50 or 45CFR46)ICH GCP 1996There are reasons we put so much emphasis on the Informed consent process. We are not going to discuss the historical reasons today but there are some references.
67Informed ConsentICH Guidelines for Good Clinical Practice (ICH E6) Defines Informed Consent: “A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is a documented by means of a written, signed, and dated informed consent form”But that is not all to the documentation.
688 Basic elements of Informed Consent Consent 45 CFR 46 8 Basic elements of Informed Consent Consent 45 CFR a & 21 CFR 50.25Study involves research, purposes, expected duration, procedures and which procedures are experimentalRisk and discomfortBenefitsAlternative procedures, available therapiesConfidentialityExplanation or more than minimal riskContact numbers for questionsVoluntary, refusal, may discontinue any timePlus Clinical Trials Database if it is a qualifying study and other additional elementsThe really nice thing about our IRB forms is if you fill them out properly you cover the 9 basic elements. And the additional elements. Unforeseeable risks, Circumstances under which subject participation may be terminated, Additional costs, Consequences of decision to withdraw, Significant new findings will be provided, Approximate number of subjects in the studyBut, can’t just give CF to subject and ask to read the form to get all these basic elements. It requires a conversation and review of the information presented to ensure understanding.
69Informed Consent: the Document Use sponsor template provided with the protocol or create using IRB templates, personalize for research site8th grade reading level (lay language)Don’t cut and paste from protocol, too technicalForm should be written in 2nd person“You are being asked to take part in a research study.”Avoid pages and pages of pure textOverwhelming and intimidatingSchedule of EventsHow to create the actual consent form document. Consent Form created based on protocol.Few helpful hints.
70Informed Consent: the Process Consent obtained directly from subject or legally authorized representative BEFORE research beginsBefore any procedure related to trial is conducted - even just taking a blood pressureConsent Process involvesGiving subject adequate information concerning studyProviding adequate opportunity for subject to consider all options, responding to subject’s questionsEnsuring subject has comprehended this informationObtaining subjects voluntary agreement to participateGiving a copy of consent form to subject , keep original for study filesKeep original signed copy of consent form for files, provide copy of signed consent form to subject, file another copy in medical record if appropriate (treatment trial)
71Informed Consent: the Process ONGOING PROCESSRe-confirm consent periodically during the studyContinue to provide information as the subject and situation requiresA new, IRB approved, informed consent form must be signed every time the risk changesDon’t need to re-consent at each annual renewal UNLESS changes to the protocol require re-consentDon’t need to re-consent just because the date on CF has changed.Do need to re-consent if PI changes or contact info changes, protocol activities / visits/labs, etc have been added or deleted or basic study conduct changes. Also, for change in risk.
72Assessing Comprehension The fact that a subject signed a consent form does not mean he/she understood what was being agreed to or truly gave their voluntary consent.Ask open ended questions:What is the study about?What will you need to do in the study?What are the possible risks in the study?How long will the study last?Ask subject to tell you how they would describe to a family member the study and their participationDocument answers to demonstrate that informed consent was obtainedDoes the subject have an adequate grasp of the study? Ask questions to determine.
73Documentation of Informed Consent Review signed consent documents: ensure signatures of subject and person obtaining consent, printed names, date accurateDocument process of obtaining informed consent in source document and/or medical recordWrite narrative note of consent process: explain that subject was given the consent form and opportunity to read it; the research protocol was reviewed with subject who was given the opportunity to ask questions, and that all questions were answered; the consent form was signed before any study procedures were performed, and that a copy of the signed consent form was given to the subject.Suggest including time written consent obtained especially if study procedures performed same dayDocument the informed consent process! Document, Document, Document—if it isn’t written, it isn’t done
74Additional Forms for ICP HIPAA authorizationStorage of samplesSSN Form – signed by subject giving permission to collect SSN for paymentAssent (pediatrics) & parental permissionTranslated consent documents & interpretersShort form – used to document consent and witness for blind, illiterate, non-English speaking subjectsSee IRB SOPs and Call for guidance if these topics arise in the context of your researchTemplates available on IRB
75Health Insurance Portability and Accountability Act – “HIPAA” HIPAA is a federal law aimed at protecting health information by establishing standards for the use and disclosure of individually identifiable health information (known as Protected Health Information or PHI) created or received by a health care entity.PHI is any information about health status, provision of health care, or payment for health care that can be linked to an individual. This is interpreted rather broadly and includes any part of a patient’s medical record or payment history.When a covered entity discloses any PHI, it must make a reasonable effort to disclose only the minimum necessary information required to achieve its purpose.Most have heard of HIPAA – given the flyer at Dr.s Office and asked to sign that you are in agreement. HIPAA is a federal law designed to protect identifiable health information created, received, or disclosed by a health care entity.
76HIPAA and ResearchHIPAA requires either a patient authorization or a waiver of the authorization requirement for use of identifiable health information (PHI) for research. IRB makes determination.Most research requires a signed HIPAA Authorization form if accessing a subject’s PHI from medical record. See IRB consent form templates.IRB may waive authorization requirement forretrospective chart reviewsreviews preparatory to research"de-identified" data seta limited waiver of HIPAA authorization may be granted by IRB to identify potential subjects for recruitmentUniversity provides online HIPAA training for new employees and requires annual renewal training,HIPAA law allows for use of Identifiable Health Information for research, but requires that you either have a patient authorize its use (by signing HIPAA authorization) or that the researcher is given a waiver of authorizations by the IRB.De-identified data: If researcher uses health information from which direct identifiers have been removed, then no authorization is required but the researcher must enter a data use agreement covered with the entity that holds the records.
77UNC HCS HD-974 Request for Access to Protected Health Information for Research Purposes Information security form that covers UNCH under HIPAA to document disclosures of PHIForm required for every study that needs access to UNC medical record (WebCIS) to obtain information for research (recruitment, review of eligibility, study follow-up)Send form to UNC Hospital Medical Information Management (MIM) along with IRB approval letter, fax toSend updated form to MIM at time of annual renewalForms are NOT part of IRB application and should not be submitted to IRB (IRB application does refer to requirement)How do you access PHI for research from the medical entity – at UNC submit an HD 974.
79For a copy of this presentation & additional helpful information Please VISITFor a copy of this presentation & additional helpful informationTRACS.UNC.edU / RESEARCH CENTRALThe website where you can access a copy of the slides.Many resources available on the website