Research Recordkeeping

1. Research Recordkeeping Carole A. Hamon & Danna Carver Research Support and Regulatory Affairs 501-526-6876

2. Introduction • Accurate documentation of research activities is not an option • Incomplete record keeping yields data that is neither valid or reliable • Data that is neither reliable or valid does not support the research effort and may hinder the ability to publish • It’s the law • It’s the only ethical thing to do • Inaccurate data puts the public at risk

3. Objectives • What is Research Data? • What is Source Data? • Essential Regulations • What essential research records must be maintained? • How might records be organized • Application of information

4. Cycle of Research Data Protocol and CRFs Approved by IRB Subject Enrolled, Research Activity Recorded in Permanent Record Research Staff Copy Data to CRFs from Source CRF Data is Monitored Data is Analyzed and Published

5. Essential Regulations: The Impact on Record Keeping

6. “The Regs” • Code of Federal Regulations • Common Rule • Drug and Device Regulations • International Code Of Harmonization • Overseen by • DHHS, OHRP, NIH, ORI, ORO

7. The Common Rule • 45 CFR 46 • Common to most research with governmental funding – covers • IRB functions • Informed consent • Vulnerable populations • Investigator responsibilities

8. Good Clinical Practices (GCP) • 21 CFR 50, 54, 56, 312, 314, 812, 814 • Called the “FDA regs” • Regulations centered around drugs and devices and their marketing approvals • Deal with safety and efficacy • Addresses financial conflict of interest and Electronic records Regs available at http://www.uams.edu/orc/Links/Links.htm

9. ICH Good Clinical Practices • Guidelines for essential documents in all types of studies • Extremely helpful with the organization of study records • International standard for Good Clinical Practices for drug approval by FDA and European Drug agencies

10. Essential Study Documents • The ICH (International Conference on Harmonization) Good Clinical Practice Guideline, Part 8: • “Essential Documents for the Conduct of a Clinical Trial” • Published in the Federal Register May 9, 1997 • Available at www.ich.org

11. Which rules apply to my research?

12. Key Types of Study Records

13. Key Types of Study Records • Regulatory File (Investigator’s File) • Source Documents • Study Conduct and Supplies ,CRFs or Data Recording Documents • Subject/ Research Files • Test Article Accountability Files • Confidential & Financial Documents

14. Typical Organization of Files • “Reg” Binders aka Investigator Files • IRB correspondence • Sponsor correspondence • FDA correspondence • Other information • Source Documentation • Research Subject File • Includes Case Report Forms

15. Investigator Files (Reg Binders)

16. Investigator Files (Reg Binders) • ALL approved versions of: • Study Protocol • Grants or Merit Reviews and updates • Investigator’s Brochure (if FDA IND) • Consent Forms • Advertisements, other study tools • ALL Correspondence with: • IRB Correspondence (including SAEs, Cont. Reviews, Deviation reports and Approval letters) • Industry sponsor • regulatory bodies (FDA)

17. Investigator Files (Reg Binders) • FDA form 1571 & 1572 (FDA drug studies) • Sample data forms or CRFs • Lab Certifications (CLIA & CAP) • Data Safety Monitoring logs • All study agreements & Contracts (NOT BUDGETS) including • Those with other institutions • Confidentiality/disclosure agreements

18. Investigator Files (Reg Binders) • For all personnel: • Training Records (HSP & HIPAA) • CVs and License • Signature logs • Delegation logs, organizational charts • Financial Disclosure Forms (FDA #3454) • Study SOPs

19. Source Documents If it was not documented, it was not done.

20. Source DocumentsFDA 21CFR 312.62 (b) An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation.

21. Source DocumentsFDA 21CFR 312.62 (b) Case histories include the case report forms and supporting data…signed and dated consent forms, any medical records, …progress notes…,the individuals hospital chart(s), and nurses notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

22. Source Documents – ICH 1.52 Original documents, data and records (e.g. hospital records,clinical and office charts, laboratory notes, memoranda, subjects’ dairies or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the –pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial)

23. Source Documents • “Where you wrote it down first”. --Antonio El- Hage Branch Chief, GCPII FDA

24. Source Documents • The documents that support what was recorded in the study as the actual research data or measurement • This may become confusing in trials that are poorly organized. • Just remember – You must have a source to validate ALL data you are using as research. That source must be available to all those reviewing the research.

25. Examples of Source Documents • Initial History and physical noting eligibility • Written records of ALL research procedures, including questionnaires, diaries, follow up • Lab, pathology reports, ecgs, x-ray reports and any other diagnostic information • Randomization Records • Record of drugs dispensed or devices used • Record of retained body fluids/tissue samples • Document location and identification of retained samples

26. So…Why all the fuss about source documents? • Incomplete or missing source documentation • Makes research data unsupportable • Raises the suspicion regarding the integrity of the data • May cause the IRB, or sponsor to ask that data be disallowed • May have put the subject at risk

27. Source Documents Sanity Tip • Keep copies of important source documents in the subject file. • Know where the originals are located • The extra effort you take to make the file complete, will be paid back a million times. • Don’t take shortcuts here!

28. Study Record Corrections • Thou Shalt NOT: • Use white-out • Obliterate an entry • Use different colored inks • Let the monitor write on the CRF • Sign the investigator’s or any other name

29. Study Record Corrections • Thou SHALT: • Make one line through the entry • Write the corrected entry beside it • Initial, date, and time the correction • Be able to see the incorrect entry

30. Study Conduct and Supply Files

31. Study Conduct and Supply Files • Patient Scheduling and Follow up* • Screening and Enrollment Logs* • Patient educational tools • Organizational Management & Contacts • Lab Normal Values * • Equipment maintenance records* • Study signature and delegation logs* *Not an option

32. Case Recording Forms • Forms used to record the information derived from study activities that will be used as data • CRFs are NOT source documents unless stated as such in the study protocol • CRFs require a supporting source document to assure the validity of the data recorded • The IRB now requires CRFs for all studies – submit with initial review

33. CRF Tips • Do not let monitors write on CRFs • In investigator-initiated studies, create and pilot forms before the study begins • Record data from the source onto CRFs in real time- do not depend on chart review for data collection! • Do not collect data if IRB has not approved • Know the difference in a CRF and source!

34. Making Your Own CRFs • DON’T • Rely on yes/no checklists • Make scribble notes on the CRFs • Copy CRFs, use them as flow sheets, and then try to cite them as source documents. • DO • Refer to the location of the source data on the CRF • Sign, initial and date ALL entries • Have PI sign and date all CRFs – meet on regular basis with your PI

35. Source vs. CRF Direct quote from an FDA letter: “Failure to maintain adequate and accurate case histories [21 CFR § 312.62(b)] You failed to ensure that data required on the Case Report Forms (CRFs) was transcribed from the study records…”

36. Subject Binder

37. Subject Binder Each subject must have a unique record for each step of the research. It should contain: • All original signed informed consent documents • Informed consent process documentation • A signed HIPAA authorization and privacy notice • A record that Inclusion/Exclusion criteria were considered • ALL case reporting or data forms, signed, dated and complete. • Source documentation • The subject identification number and study number

38. Subject Binder, cont. • Record of subject withdrawal and reason for withdrawal • All communication with subject • Include phone calls and correspondence, original diaries, etc • Schedules of ALL research procedures, and follow up appointments • Copies of Lab, pathology reports, and any other diagnostic information • Copies of record of drugs dispensed or devices used

39. Subject Binder, cont. • PI report of Adverse Events • PI report of Protocol Violations • PI reports of Protocol Deviations • PI reports of Deaths Reports must be sent to the IRB AND the Sponsor. Keep a copy of those in the file, along with the record of when they were sent.

40. Test Article Binder

41. Test Article Accountability An Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. CFR 21 part 312.62a Includes prescribing and accounting for returned or unused drugs or devices.

42. Test Article Accountability • This is more important than balancing you checkbook or doing your taxes • It can send you to the nut house if not done correctly • Document in a timely fashion and consistently

43. Test Article Definition ...any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the Public Health Service Act. CFR 21 part 56.102(l)

44. Drug Accountability • Begins with a correctly written prescription which includes: • Identification of study (IRB#) • Specific supply the drug will come from • Identification of subject • Correct administration information • Prescribed and signed ONLY by a study physician or APN listed in ARIA as an approved investigator

45. Test Article AccountabilityRecords for Drugs and Devices • ALL shipping and receiving invoices indicating the type and quantity of the drug or device, and the date of shipment • Expiration dates • Record of dispensing, waste and return reflecting the subject, reason and batch or lot number • Wastage done according to institutional policy

46. Test Article AccountabilityRecords for Drugs and Devices • Storage conditions (temp logs) • Records showing only appropriate personnel dispensed the drug or used the device according to protocol* • Pharmacy correspondence for investigational drugs *Should be listed as “key study personnel” On the signature log

47. Test Article AccountabilityRecords for Drugs and Devices • Drug or device was used only after patient signed an informed consent • Information/educational materials were given to patients • Unique lot numbers for devices are recorded in patient hospital chart

48. Test Article Absolutes • Sponsors may not ship test article to subjects • Sponsors may not ship to study site without IRB approval • Study sites are not allowed to receive drugs from anyone but the sponsor • If protocol requires shipping to subject, study site must do it • Pharmacy MUST be involved

49. Test Article Sanity Tips • Always know the “count and the amount” • Do not allow anyone but authorized personnel access to test articles • Return unused drug or empties as often as possible (Get monitor to help during monitor visits) • Document dispensing and shipping immediately • Inventory new shipments on arrival • Make sure you will be there when shipment arrives • Check expiration dates • Document how unused article was wasted

50. Confidential & Financial Records