Study Organization/Management and Form Design Considerations

1. Study Organization/Management and Form Design Considerations Holly J. Smith Center for Biostatistics and Advanced Informatics

2. Study Organization and Management

3. Why is study organization and management important? • Good study organization and management is essential to helping ensure that the study is being conducted, recorded and reported in compliance with the study protocol, study SOPs, Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) guidelines.

4. Whose line is it anyway? • Identify and understand roles of personnel involved in the research team • Principal Investigator • Co-investigator • Study Coordinator/Research Nurse • Biostatistician (if applicable) • Pharmacist (if applicable) • Clinical Research Associate/Monitor (if applicable)

5. Principal Investigator Principal Investigator (PI) – responsible for overall conduct of research at the site and is expected to comply with the Code of Federal Regulations (CFR) and the International Conference on Harmonisation Guidelines for Good Clinical Practice (ICH/GCP). For each research project a PI must sign the Form FDA 1572

6. Principal Investigator (cont.) • Conduct the study according to the protocol and will only change the protocol after first notifying the sponsor (except when necessary to protect the safety, rights, or welfare of subjects). • Personally conduct or supervise the described investigation. • Inform participants that agents are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and the institutional review board (IRB) review and approval in 21 CFR Part 56 are met. • Report to the sponsor and HSC any and all adverse events that occur during the study in accordance with 21 CRF 312.64. • Read and understand the information in the investigator’s brochure. • Ensure that all personnel involved in the study understand their obligations regarding the study. • Maintain adequate and accurate records in accordance with federal guidelines and that the records are ready for audit (21 CFR 312.62, and 312.68). • Ensure that their IRB complies with federal guidelines (21 CFR Part 56).

7. Study Coordinator / Research Nurse Study Coordinator or Research Nurse – A well executed protocol is often due to an organized, responsible study coordinator or research nurse. The following tasks are often delegated to the study coordinator or research nurse. These tasks include: • Prepare regulatory documentation (IRB approval, IRB-approved informed consent, additional certifications defined in the protocol, etc.). • Ensure the study is conducted in compliance with protocol requirements. • Maintain IRB correspondence and regulatory documentation. • Recruit potentially eligible participants for clinical trials and evaluate participant for protocol eligibility. • Meet with the study participant to review the details of study enrollment. • Ensure that informed consent has been obtained before initiating research-related activities. • Develop strategies to retain study participants on a clinical trial. • Schedule tests and appointments for participants on clinical trial within timeframes required by protocol. • Complete prescriptions/orders/requisitions for the investigational pharmacist and lab personnel, if applicable

8. Study Coordinator / Research Nurse(cont.) • Complete Case Report Forms (CRFs) accurately, and retain a copy in the CRF Notebook or Study Binder. • Maintain source documentation for each study participant. • Instruct and educate participants regarding study treatment modalities and anticipated side effects and the management of their symptoms. • Provide guidance to the Principal Investigator, pharmacist, and participant on dose adjustments based on the protocol dose modification section. • Inform pharmacist about any dose changes. • Collect returned study drug and monitor participant dosing compliance. • Identify and document adverse events and serious adverse events (SAEs). • Initiate Serious Adverse Event Reports (SAEs) and obtain the PI’s signature within the proper timeframes and notify proper individuals stated in the protocol. • Submit protocol amendments and case report forms to the sponsor for review, if applicable. • Identify and document protocol deviations. • Respond to data queries in a timely manner • Update PI on study status • *NOTE: The PI is responsible for the research conducted at the site, even if select tasks are delegated to the study coordinator, research nurse, pharmacist, etc.

9. Pharmacist Pharmacist – Designated staff member that is accountable for: • Study drug supply, storage, preparation, dispensing, and disposal or return • Accountability records and record security Retain: • Instructions for ordering study drug • Shipping receipts and return record • Drug Accountability Forms • Transfer Forms • Medication administration record • Maintenance of integrity of blind • Instruction to the PI and study coordinator/research nurse on the proper method of drug administration

10. Clinical Research Associate / Monitor Clinical Research Associate (CRA) – A qualified person by training and experience, who is responsible for ensuring that clinical trials are conducted according to the Code of Federal Regulations and the ICH/GCP guidelines. The CRA is responsible for verifying/assuring: • The acceptability and accuracy of the Investigator and the site’s qualifications. • The acceptability of the agent storage facilities, adequacy of clinical supplies, and initial and ongoing acceptability of the site facilities. • Participants are given investigational agents according to the dosing specified in the protocol and the necessary instructions on properly using, handling, storing and returning of the study drug. • The receipt, use, and returns of the investigational agents are controlled and documented correctly. • The appropriate disposition of unused clinical trial supplies.

11. Clinical Research Associate / Monitor(cont.) • Study staff complies with the protocol, regulatory requirements, and GCP/ICH guidelines. • Informed consent was obtained prior to each participant’s participation in the trial. • Study staff received all necessary and appropriate trial documents and supplies to enable the smooth conduct of the trial. • PI is enrolling only eligible subjects. • Accurate reporting of the enrollment rate. • Accurate, complete and current source documents and trial records are kept. • PI provides all the required reports, notifications, application, and IRB submissions and those documents are accurate, complete, timely, legible and dated. • Accuracy and completeness of the CRF relative to the source documentation. • Appropriate reporting of Adverse Events (AEs) and SAEs. • Protocol deviations/changes are documented and reported to the sponsor and the IRB. • Significant protocol deviations are reported to the Investigator and appropriate action taken to prevent the recurrence of this type of deviation.

12. Study Organization: Pre-initiation • Documentation • Signed Form FDA 1572 (all versions) • CVs of principal and all co-investigators listed in 1572 • Investigator’s brochure • IRB Approval/Correspondence with the IRB and/or Sponsor • IRB Letter of Assurance / IRB Membership Roster • IRB Approved Consent Form • Laboratory Certification (CLIA and CAP) and Normals

13. Study Organization: Pre-initiation (Cont.) • Administrative • Contract • Budget (IRB costs, pharmacy, study coordination, data management, analytical support, pathology, supplies, procedures, drug, laboratory costs, shipping, radiology, advertisements, subcontracts, etc.) • Subject Recruitment • Department Meetings • Advertisements (need IRB approval if public) • Notifications to physicians

14. Study Organization: Pre-initiation (Cont.) • In-service • Pharmacy • Nurses • Physicians • Clinical Data Managers • Laboratory Personnel

15. Study Organization: Pre-initiation (Cont.) • Protocol Execution Preparation • Visit / Clinic Worksheets • Patient / Subject Log • Protocol Summary (Contacts, purpose, inclusion and exclusion criteria) • Drug Administration Summary (Contacts, Adverse effects, Administration, Dose reduction rules) • Study Specific Laboratory and Procedural Requisitions • Pre-completed Orders (As appropriate) • Randomization list / envelopes, etc. (As appropriate)

16. Study Organization and Management: Active Study • Changes in Investigators, Laboratories, etc. Listed on Form 1572 • Form FDA 1572 revised and signed • IRB and Sponsor (if applicable) notified of change • IRB and Sponsor (if applicable) acknowledgement and approval of change • Copy of revised 1572 and IRB and Sponsor notification, approvals and/or acknowledgement filed in regulatory binder (i.e. study files)

17. Study Organization and Management: Active Study (cont.) • Protocol and Consent Form Changes / Amendments and Safety Updates • Amendment memo from investigator or sponsor • IRB amendment memo / form notifying them of revision or update along with revised protocol pages (or entire document) and consent form reflecting changes (if applicable) • Approval letter for each revision / change from IRB prior to instituting change • Copy of approved revised consent form • Copies of memos to IRB, IRB approvals and relevant documents on file in regulatory binder (i.e. study file) • Copies of IRB approval and approved revised consent (if applicable) to sponsor

18. Study Organization and Management: Active Study (cont.) • Protocol Deviations • Occur when some aspect of patient treatment and/or evaluation are not consistent with the protocol • Classification of deviations • Protocol Violations • Minor Deviations • Major Deviations • Most common types of protocol deviations • Ineligible Patients • Non-Compliance and Incomplete Evaluations

19. Study Organization and Management: Active Study (cont.) • Drug Accountability • Shipping records filed in regulatory binder (pharmacy may keep these records) • Drug accountability records update as appropriate (if managed by pharmacy, must be available during an auditing/monitoring visit) • Drug storage, preparation and administration instructions • Drug unblinding instructions (if applicable) • Documentation of unblinding (if applicable)

20. Study Organization and Management: Active Study (cont.) • Correspondence / Meetings • Copies of all letters, emails, memos, faxes written and received on file in the regulatory binder • Forms and procedural manuals • Newsletters • Site Visit logs / Monitoring log on file • Telephone logs maintained

21. Study Organization and Management: Active Study (cont.) • Sensitive Data (limited access / secure area) • Copies of informed consent from each patient/subject on file • Laboratory data and other procedural reports (EKGs, blood tests, diagnostic test films, etc.) that contain patient identifiers • Patient / Subject logs • Any documentation that contains a patient name

22. Study Organization and Management: Active Study (cont.) • Essential documents in a regulatory binder IRB approvals • IRB annual renewals • IRB approved informed consents • Form FDA 1572 • Laboratory certificates (CLIA and CAP) • Laboratory normal ranges • Screening logs, subject logs, randomization logs • Safety report and memos with appropriate IRB correspondence • Current medical licensures • Human subjects and HIPAA training

23. Study Organization and Management: Study Close Out / Termination • Copies of all regulatory documents as listed previously • Drug inventory completed, including drug return forms • Return drug to sponsor or dispose of as directed • Case Report Forms completed, signed, and copies to sponsor • Data entry and data cleaning completed, as appropriate • Ship any remaining banked specimens • Final Report

24. Data Collection Forms and Data Management

25. Data Collection Forms • Purpose of Forms • To collect relevant study related data that is needed to answer the research questions and analysis • This also ensures appropriate evaluations and procedures are completed per protocol

26. Data Collection Forms (cont.) • Common Problems in Form Design • Too much data is collected on each patient • Forms are not clear as to the precision of data and information needed • Data is not recorded in manner that is compatible with database and data management applications or statistical applications

27. Data Collection Forms (cont.) • Common Types of Forms and Worksheets • Eligibility Checklist • Baseline Assessment Forms (i.e., demographic, baseline medical history, baseline review of systems, baseline symptom review, baseline adverse events) • On Study Evaluation Forms (i.e., follow-up forms, cycle or visit specific forms, questionnaires, toxicity assessment, response forms) • Off Treatment Forms (i.e., termination forms, completion forms, long-term follow-up forms)

28. Data Collection Forms (cont.) • Design and Layout of Forms • Principal aim in data collection forms is for statistical analysis – not for the perusal of individual experiences • Questions should be constrained so that the answer can be given in numerical form or multiple choice such that the answers can be coded for analysis in numerical form • Blanks should be provided to give specific guidance as to appropriate data to be completed (temp., BP, dates, etc.) and items requiring decimal places need to be clear as to the location of the decimal • Units should be stated next to questions not included in fillable portions of the data collection forms

29. Data Collection Forms (cont.) • Design and Layout of Forms (cont.) • Some items seek qualitative rather than quantitative measurements- in this case a number scheme should be assigned to these responses (1=male, 2= female; 0=no, 1=yes, etc.) • Other questions may involve the recording of time intervals or dates. Recording of actual dates is preferred and is more accurate survival and time to event data analysis • Golden Rule: Every question should require insertion of a number or letter or NA in the appropriate space. This allows one to easily determine whether the data is missing or someone failed to complete.

30. Data Collection Forms (cont.) • Design and Layout of Forms (cont.) • Wording of questions should be straightforward and have only one single possible answer • Instructions for proper form completion should be located at the top of the form for patients or in a separate training manual for the nurses, clinical data managers or clinicians • Form layout: should flow well for the person completing the form

31. Examples of Poor Data Collection Form Design

32. Examples of Good Data Collection Form Design

33. Data Collection Forms (cont.) • Design and Layout of Forms (cont.) • All forms should be validated and pre-tested before official use: this includes the administration of, completion, review, data entry and data management • Form design is a collaboration between the clinical investigator, data entry personnel, the study coordinators completing the forms, data management and analytical personnel

34. Data Management and Quality Control • Prior to analysis all data needs to be collected, checked for completeness, accuracy and organized • General data management: have the collection forms been submitted at the correct time or in a timely fashion, are all previously required forms on file, is the patient trial number correct, etc. • Missing data checks: are there specific items or whole sections left blank • Range checks: do values for each question fall within appropriate range of replies • Logic checks: are there any inconsistencies in replies to different questions, e.g.. Is there data of randomization prior to birth date, is diastolic BP > systolic BP

35. In Summary • Good study management is essential to conducting your study in compliance with the protocol as well as with federal guidelines. If the study conduct is compromised not only is the PI and institution accountable but ultimately subjects/patients can be put at undue risk. • Proper form design and collection of data helps to ensure the credibility and integrity of the data. Without quality data to analyze, the effort and expense for your research was for not.