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Orientation for New Clinical Research PERSONNEL Module 2

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1 Orientation for New Clinical Research PERSONNEL Module 2
Welcome and introductions – thanks to contributors to presentation Bathrooms Presented by NC TraCS Institute UNC Office of Clinical Trials UNC Network of Clinical Research Professionals

2 Overall Agenda for Orientation
Module 1: September 12, Introduction to Clinical Research, Education, and IRB Module 2: September 19, Study Implementation, Documentation, and GCPs Module 3: September 26, Contracting and Hospital Administrative Elements Module 4: October 3, Clinical Trial Management, Budgeting, Hospital and Research Accounting Discuss 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.

3 Overall Agenda for Orientation
Module 1: Introduction to Clinical Research, Education, and IRB Module 2: Study Implementation, Documentation, and GCPs Module 3: Contracting, COI, and Hospital Administrative Elements Module 4: Clinical Trial Management, Budgeting, Hospital and Research Accounting Discuss 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.

4 Study Team Responsibilities
Michelle Duclos, NCRP

5 Principal Investigator
Ultimate administrative and fiscal responsibility for the team performance of the study subject to IRB/Institution review and oversight: The science The integrity The business operations Understanding and following the protocol as approved by the IRB is the first and most critical obligation of the investigator in human subjects research

6 Legal 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.

7 Form 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 subjects I 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 met I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR I 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.

8 Form 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 study Responsibility for assessing causality of adverse events Investigators who conduct clinical investigations of medical devices commit themselves to supervise all testing of the device involving human subjects

9 Should 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

10 Should 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

11 Investigator 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 IRB Provide the IRB with accurate and complete information and updates as the information changes Notify the IRB of all unanticipated or serious adverse events involving risk to human subjects Provide all reports required by the IRB on the timeline required by the IRB

12 Clinical Research Coordinator (CRC) What is your title?
Social/Clinical Research Assistant Social/Clinical Research Associate Social/Clinical Research Specialist Research Nurse Clinical Nurse Project Manager Research Instructor Others?

13 Primary 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 evolved The 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 detail Good Communication Skills Flexibility Ability to work independently Organizational skills

14 Shared 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 subjects Recommend reviewing and understanding the Guidance for Industry – investigator responsibilities – protecting the rights, safety, and welfare of study subjects.

15 FDA Final Guidance Guidance 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, and To protect the rights, safety, and welfare of study subjects

16 General CRC Responsibilities Protocol Evaluation
Subject availability Personnel requirement Equipment & facility availability Develop timelines Propose & negotiate alternatives to improve implementation The CRC may Review the new protocols to evaluate the feasibility of conducting the study at the site (for industry sponsor studies) Development of a study budget Prepare

17 General Responsibilities Administrative
Interact with IRB, lab staff, clinic staff, pharmacy, nursing homes, assist living, churches, community centers, etc Prepare IRB documents including ICF Prepare Study Budget Assure all documentation is maintained Interact with Sponsor Interact with PIs and sub-investigators Coordinate and participate in monitoring visits with sponsor Complete CRFs and submit to sponsor Resolve data queries Facilitate inspections/audits Document study progress

18 General CRC Responsibilities Study Subjects
Recruit study subjects Assess subjects for eligibility Discuss study with subject Obtain informed consent Schedule subject visits/assessments Assure all study tests and visits are done at appropriate time intervals Final 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.

19 General CRC Responsibilities Study Subjects
Evaluate study subjects at appropriate intervals Assess laboratory data and clinical signs for potential adverse events Adverse Events (AEs) Assist PI with gathering information to help PI determine classification, and causality Observe and document AEs Act on PI’s recommendation Maintain follow-up until reconciliation Communication with sponsor Ultimately 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.

20 General CRC Responsibilities Study Subjects
Provide information for treatment and reactions Administer or dispense investigational agent, as outlined in the protocol, under the investigator’s supervision Investigational Drug Accountability Order, store, dispense, retrieve, log Randomization codes Unblinding procedures Promote subject compliance by providing patient support and education Prepare lab specimens; ship biological samples and radiologic films Arrange for study subject compensation Comply with FDA regulations for conducting clinical trials

21 Study Implementation Michelle Duclos, NCRP

22 Protocol Implementation

23 Protocol Implementation
Research Site – Study start up meeting, documentation of training of all individuals listed on delegation log Notification to providers, nurses, clinic staff, and other team members of upcoming research protocol Pre-identification of potential subjects – Once IRB approval received, contacting potential subjects regarding participation in research protocol Development of a recruitment plan Organization of study materials Creation of source documents

24 Protocol Implementation
Organization of study materials Regulatory binder IRB binder Correspondence binder Protocol binder Investigator brochure binder IVRS information Supply Order forms Investigational Drug Study Manual

25 Is this how your office looks?
Patient Research Charts If 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.

26 Protocol Implementation
Creation of source documents Helpful hints: review your study visit schedule review the Case Report Forms or eCRFs to ensure you collect all information that will be documented on CRF Develop standard forms for department that can be used across studies. Examples Physical Exam form Medical history form General Research Record or SOAP note Documentation of Informed Consent Template Templates available on TraCS or OCT website – Marie will talk about next

27 Depending 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 processes Increases communication of all team members Organization of task needed, when managing multiple protocols

28 Recruitment A 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 campaign TV, Radio, Print, Website Dear Doctor Letters –fax or local providers, recommend follow-up with a meeting if you want practice to help Direct to Patient from databases Posters, Pamphlets, Mailings (letters, post cards) Determine if Carolina Data Warehouse can be utilized Develop a phone screen/script as necessary for phone calls Social networking opportunities Community events (fairs, flea markets, senior centers) Develop a UNC mass Communicate internally with departmental doctors for referrals, develop a system in department for identification of potential subjects Communicate with NC TraCS Talk about cost of varies recruitment campaigns Talk about whether pharma company offerring central campaign – pros and cons - you still need to have a plan at your site Talk about our internal system to give an example

29 Good Clinical Practices & Study Documentation
Marie Rape, RN, BSN NC TraCS Institute Documentation in your study files and end with the informed consent process

30 Good 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 Guidance Lets 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 and applicability 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??

31 E6 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 Practice Several 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

32 Topics Covered in ICH GCP
Describes: Qualification of an investigator Education and training of study staff Delegation of study-related tasks Requirement for IRB review Compliance with the protocol Responsibility for investigational product accountability Informed consent Safety reporting Trial management & record keeping Data quality and integrity, quality control Essential documents for a trial Show 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).

33 Why 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 subjects Ensure accuracy and credibility of the data and reported results Ensure conduct of the trial is in compliance with: the protocol/amendment(s) currently approved by the IRB applicable regulatory requirements institutional policies all applicable rules and regulations Adherence 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).

34 Who 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.

35 Documentation Once 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 documentation Resources, 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).

36 FDA 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 investigation case 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) investigation FDA 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.

37 Source Documents Source 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 E6 The first place something is recorded is considered the source document for that clinical trial activity A “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.

38 Types of Source Documents
Medical history Hospital records Clinic & office charts Progress notes Lab notes Memoranda Meeting minutes Notes to file Phone records Subject diaries Questionnaires Subject files or records Drug dispensing records Recorded data from automated instruments (DynaMap, ECG, EEG, ) X-rays, scans, MRIs Examples of source documents to support research Examples of supporting data: consent form, progress notes of MD, nurse notes Source documents are part of the supporting data Essential that there be consistency across the records

39 Example of a source document?
Subject ABC 3/1/06 Is 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.

40 Case 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 documents If 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.

41 Important 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-adherence Completion of all protocol-required tests, procedures Missed visits, subject contacts, procedures, or examinations Protocol 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 IRB Subject 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.

42 Templates Improve Source Documentation
Some research data collected on Hospital based forms as part of medical care: Vital signs on clinic record sheet Medication administration on MAR for inpatients, Laboratory tests History and physical exam Other 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

43 Example 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.

44 I / 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 criteria Documentation of Eligibility Important! Keep supporting documentation that demonstrates that subject meets criteria (e.g., colonoscopy results to demonstrate normal colon)

45 Sample Inclusion/Exclusion Criteria Checklist
All Inclusions should be written to answer “yes” and All Exclusions should be written to answer “no” to avoid confusion.

46 Signature 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

47 Eligibility Criteria IRB 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 data Investigator may wish to enroll a subject who does not precisely fit the eligibility criteria PI must obtain IRB approval for the change in eligibility criteria May 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 enrolled Enrolling 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 regulations Enrolling 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.

48 Enrollment Note Template
Study IRB #: Principal Investigator: Subject Name: ___________________ ID#: ___________ Yes No 1. 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 ________

49 Note to File Template A 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

50 Template 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 __________

51 Telephone Contact Log Study ID __________ Subject ID __________
Date/Time Incoming/ Outgoing Message/ Conversation Comment Incoming Message All 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.

52 Helpful 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 later Describe 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 closed Following 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)

53 ALCOA* 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 Meeting ALCOA is a term used to describe data quality of study documentation. If have poor data quality, you will have poor results from your study.

54 Maintaining Regulatory Files
Essential Documents for conduct of Clinical Trial should be maintained together in a Regulatory Binder Purpose of Regulatory Binder: Organize essential documents Allows research team to reference information Allows easy access to documents by monitor, auditor, IRB, FDA, OHRP Principal Investigator ultimately responsible for maintenance of Regulatory Files, but task often delegated to other member of research team One component of the study files is the Regulatory Binder. Essential Documents outlined in GCP document.

55 Regulatory Binder (Essential Documents)
Signature logs (DOA and monitoring log) Screening/enrollment logs Protocol and amendments Investigator’s Brochure Sponsor correspondence Training 1572, Conflict of Interest, CV’s, Licenses, Financial Disclosures IRB membership, FWA IRB approvals and correspondence AE log, SAEs IND Safety Reports Local Laboratory CLIA/CAP, normal values, Lab Dir. CV Temperature Logs Subject ID Code List Essential Documents is another term used to refer to the contents of a Regulatory Binder Key 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 binder IRB binder Correspondence binder Protocol binder Investigator brochure binder

56 Delegation 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 samples B) 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/Maintenance Study Personnel Printed Name Title Study Personnel Role (e.g. PI, Investigator, Coordinator, Pharmacist, etc.) Responsibilities* (List all letters that apply) Signature of Initials of Study Personnel Obligation PI Signature & Date (To acknowledge roles & responsibilities) IRB Approved Start Date End Date

57 Monitoring Log Should document when monitoring is performed and what was monitored. From Office of Clinical Trials

58 Screening and Enrollment Log
Patient Name Telephone Pre-Screen Date Potentially Eligible ? Screenin g Visit Date Study ID Number Consented/ Enrolled ? Eligibility * Staff Initials Yes No Yes No  Screen Failure, Reason: Date:  Eligible Yes No Another 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.

59 Protocol Deviation Log
Another template/form that can be used to document protocol deviations, if you don’t have one provided by your sponsor. From

60 Adverse Event Tracking Log
Principal Investigator: HRC Protocol #: Study Title: # Subject ID Date of Event Date PI Aware Description of Event Serious Non-serious Expected Unexpected Severity Scale (CTCAE) Relatedness Date Reported to IRB, if applicable Date of IRB Review Other 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Often 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.

61 Documentation of AEs and UPs
Keep log of AEs, SAEs, Unanticipated Problems Track 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 scale Decisions 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

62 Templates Available for Documentation (NCRP or NC TraCS)
Delegation of Authority (Responsibility) Log Protocol Modification Tracking Adverse Event (UP) Tracking Protocol Violation Log Memo to File Progress Note Template Screening and Enrollment Log Telephone Log Investigational Drug or Device Accountability Consent Process Documentation

63 Informed consent process
Claudia Christy, NCRP & NC TraCS Institute

64 Informed Consent Process

65 Objectives Review regulatory requirements for Informed Consent
Review the Informed Consent Process Review documentation of the Informed Consent Process Review additional required forms for the Informed Consent Process

66 History Historical Nuremberg Code 1947
Declaration of Helsinki 1964 Belmont Report 1979 Code of Federal Regulations (21CFR50 or 45CFR46) ICH GCP 1996 There 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.

67 Informed Consent ICH 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.

68 8 Basic elements of Informed Consent Consent 45 CFR 46
8 Basic elements of Informed Consent Consent 45 CFR a & 21 CFR 50.25 Study involves research, purposes, expected duration, procedures and which procedures are experimental Risk and discomfort Benefits Alternative procedures, available therapies Confidentiality Explanation or more than minimal risk Contact numbers for questions Voluntary, refusal, may discontinue any time Plus Clinical Trials Database if it is a qualifying study and other additional elements The 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 study But, 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.

69 Informed Consent: the Document
Use sponsor template provided with the protocol or create using IRB templates, personalize for research site 8th grade reading level (lay language) Don’t cut and paste from protocol, too technical Form should be written in 2nd person “You are being asked to take part in a research study.” Avoid pages and pages of pure text Overwhelming and intimidating Schedule of Events How to create the actual consent form document. Consent Form created based on protocol. Few helpful hints.

70 Informed Consent: the Process
Consent obtained directly from subject or legally authorized representative BEFORE research begins Before any procedure related to trial is conducted - even just taking a blood pressure Consent Process involves Giving subject adequate information concerning study Providing adequate opportunity for subject to consider all options, responding to subject’s questions Ensuring subject has comprehended this information Obtaining subjects voluntary agreement to participate Giving a copy of consent form to subject , keep original for study files Keep 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)

71 Informed Consent: the Process
ONGOING PROCESS Re-confirm consent periodically during the study Continue to provide information as the subject and situation requires A new, IRB approved, informed consent form must be signed every time the risk changes Don’t need to re-consent at each annual renewal UNLESS changes to the protocol require re-consent Don’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.

72 Assessing 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 participation Document answers to demonstrate that informed consent was obtained Does the subject have an adequate grasp of the study? Ask questions to determine.

73 Documentation of Informed Consent
Review signed consent documents: ensure signatures of subject and person obtaining consent, printed names, date accurate Document process of obtaining informed consent in source document and/or medical record Write 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 day Document the informed consent process! Document, Document, Document—if it isn’t written, it isn’t done

74 Additional Forms for ICP
HIPAA authorization Storage of samples SSN Form – signed by subject giving permission to collect SSN for payment Assent (pediatrics) & parental permission Translated consent documents & interpreters Short form – used to document consent and witness for blind, illiterate, non-English speaking subjects See IRB SOPs and Call for guidance if these topics arise in the context of your research Templates available on IRB

75 Health 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.

76 HIPAA and Research HIPAA 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 for retrospective chart reviews reviews preparatory to research "de-identified" data set a limited waiver of HIPAA authorization may be granted by IRB to identify potential subjects for recruitment University 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.

77 UNC 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 PHI Form 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 to Send updated form to MIM at time of annual renewal Forms 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.

78 Questions?

79 For a copy of this presentation & additional helpful information
Please VISIT For a copy of this presentation & additional helpful information TRACS.UNC.edU / RESEARCH CENTRAL The website where you can access a copy of the slides. Many resources available on the website

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