Essential Documents & Source Documentation SOPs

1. Essential Documents & Source Documentation SOPs Margaret Matula, R.N., M.G.A. Nurse Consultant Clinical Research Management Branch TRP/DAIDS/NIAID/NIH e-mail: mm154j@nih.gov phone: 301- 402- 2302

2. Principles • Ensure data quality • Create an audit trail • Verify all data

3. Local Requirements Always refer to local, state, institution, and IRB/IEC policies and procedures.

4. Essential Document SOP

5. Definition: Essential Documents • Permit evaluation of: • Conduct of a trial • Quality of the data • Generated throughout various stages of a trial: • Before the trial begins. • During the conduct of the trial. • After completion or termination of the trial. • Serve to demonstrate compliance with: • Standards of good clinical practice (GCP). • All applicable regulatory requirements. • Audited/inspected by sponsor and regulatory authorities.

6. IRB Approvals – revised • Dated proof of IRB/IEC submission of the following for both initial submissions and revisions (if any). Revised documents must be labeled (e.g., date and/or version number) to differentiate them from previous versions • IND Safety Reports, Safety Memos, & Safety Alerts • Investigator’s Brochures

7. Laboratory – revised • To document competence of local, central or Group laboratories to perform protocol required tests and support reliability of results of medical/laboratory/ standardized procedures/tests, one of the following must be on file: Laboratories located in the United States • CLIA Certification of Compliance • CLIA Certification of Accreditation AND the agency certificate (e.g., CAP Certification of Accreditation) Laboratories located outside the United States • Results of an established quality control and/or external quality assessment program • Other validation

8. Screening & Enrollment Logs • Pretrial screening of subjects (screening log) • Chronological enrollment of subjects (enrollment log) • Consists of: • Initials of all patients screened • PID # (if patient receives one) • Date screened • Date randomized • Indicate reason if not randomized

9. Signature Key/Log • Documents signatures of individuals using initials in place of a full signature to sign CRFs and source documents. • Documents signatures and initials of all persons authorized to make entries and/or corrections on CRFs, ie, clinicians, MDs, Pharmacists, data personnel, etc.

10. Signature Key • Key must include: • initials • printed signature • legal signature (first and last name) • credentials (if appropriate)

11. Source Documentation SOP

12. Definition: Source Document • Any original documents or certified copies that include documentation pertaining to a subject’s medical history, treatment, and condition while on a research study. • Includes but is not limited to: • Clinic chart • Medical record • Office notes • Flow sheets • Laboratory reports • Medication records • Prescriptions • Radiology reports

13. Source Document continued… • Make available for direct access all requested documentation that may be relevant to the subject’s trial participation. • Saved as: • Electronic media / computer records • Original paper documents • Certified copies

14. Informed Consent

15. Screening - revised Federal Regs and Institutional Policy must be followed when screening subjects to determine eligibility: • 1. Screening: any procedure done solely for the purpose of determining a potential subject’s eligibility. • 2. Consent must be obtained prior to invasive procedures. • Written consent required for screening unless IRB waives requirement.

16. Screening….. • 4. Either IRB approved generic screening consent or protocol specific consent is acceptable. • Screening consent must be signed before screening begins. 7. Maintain a list of subjects screened for a protocol. • If site uses screening consents, protocol consent must be signed prior to randomization. 6. Review of medical records and/or databases to identify potential subjects outside the institution is not permitted without prior consent of potential subjects.

17. Screening Find out how HIPPA is going to impact screening activities at your site!!

18. Special Populations • Refer to 45 CFR 46 for special requirements of obtaining informed consent of special populations in research. • Pregnant women, fetuses, and neonates (subpart B) • Prisoners (subpart C) • Children (subpart D) • Includes adolescents

19. Other Special Populations….. • Non-English Speaking • Information given to subject must be in language they understand— • Refer to the regulations: 45 CFR 46, Subpart A and 21 CFR 50. • OHRP guidance:http://ohrp.osophs.dhhs.gov/humansubjects/guidance/ic-non-e.htm • FDA guidance:http://www.fda.gov/oc/ohrt/irbs/informedconsent.html#nonenglish

20. Requirements • Consent must be documented on a written consent form. 2. All consent forms must be approved by IRB. 3. All consent forms must be submitted to DAIDS for review. • All consent forms for new protocols and amendments must be approved by DAIDS. • Protocol-specific consent must be obtained prior to randomizing/enrolling subject.

21. Signatures • Must be legal name. 2. Must not use initial for last name. 3. Strongly recommend not using an initial for first name. 4. Must be in ink. • Must be dated by each person signing the form (It is NOT acceptable for research staff to complete the date for another signer).

22. Signatures • Must be legal name. • Sites are not expected to routinely verify a person’s legal name; however, if the site becomes or is aware that a person has not used his/her legal name to consent, then the following must be done: • Obtain a new, signed consent with the legal name. • Notify the local IRB/IEC. • Document the events in the research record and the actions taken by the site. • Ensure that there is documentation linking the two names. • For monitoring and audits, the site must be able to show that the names refer to the same person, (i.e., John Doe is really John Smith). • Follow local institutional/IRB policy regarding continued use of the alias.

23. Signatures • If a subject is not able to write or sign his/her name in the form of a traditional “signature” as indicated above: • If permitted under state/local law or institutional/IRB policy, document in the research record that the person cannot sign his/her name and that it is their “mark”. • Also refer to the bullet on illiterate persons in this section.

24. Case Report Forms (CRFs) as Source Documents (SDs)

25. CRFs – revised • Requirement to maintain a list of the CRFs being used as source documentation. • Requirement to sign/initial and date the original CRF as you would any other source documentation. • Suggestion about the use of the SAE form as a source document.

26. Copies: certified

27. Copies: Certified – revised It is a suggestion, NOT a requirement to certify copies of source documentation.

28. Source Document SOP • What’s the difference? Chart Note Flow Sheets Medical Records Research Record Source Document

29. Chart Note • All notes related to study visits • In Medical or Research Record • Recorded by Site Staff • SOP does not apply to notes from sources other than site personnel

30. Chart Note and Flow Sheets • All entries must be signed/initialed & dated • each new entry • by person making the entry • Exceptions: • multiple entries by same person/same day • single date with multiple entries by different staff

31. Medical Records • At institutions with primary care facilities • must be accessible to monitor • if missing, staff notes efforts to locate them

32. Medical Records – revised • Requirement is to obtain source documentation from outside sources to support endpoints or SAEs. • Also, DAIDS Medical Officers may request that records be obtained when investigating AEs.

33. Medical Records - revised • Suggestions: • Document all attempts to obtain records pertinent to subjects study participation • Acknowledge (in SD) when records are missing • Hospital records not held to GCP standards • Obtaining records from outside sources is driven by need to gather sufficient info for adequate clinical assessment of the subject’s medical condition.

34. Research Record • All documents that are relevant & substantiate subject’s participation in research: • IC, SD, Pharmacy. Records, CRFs, etc. • Subject consented and Investigator agreed to monitors direct access to all records. • Sites to produce record in it’s entirety: • Source of data must be verifiable in original or certified copies.

35. Research Record • Shadow Files are an adjunct: • May include: • IC, Screening, Baseline, Vitals, Clinic & Lab findings, study drug, etc. • Originals are preferred—monitors may ask for originals even if you have a shadow file.

36. Source Document • Original or certified copy • Includes: • Medical Record • Clinic Chart • CRFs used as SD • Research record • Primary Care office chart • Flow sheets, medical records, Rx, EKG • Sites must provide direct access to all requested, relevant documentation

37. Source Document No documentation for protocol required data = Inadequate Source documentation

38. Error Corrections – revised Suggestion for when it is considered necessary to give an explanation for why data were changed: • If it is something a reviewer can “see” or is obvious, such as a transcription error, then it needs no explanation. • For example, if the site corrected a lab value that was initially transcribed incorrectly to the CRF then an explanation for the correction is not necessary as long as it can be verified with the original lab report. • If it is not clear, like a diagnosis or symptom that was deleted after initial entry, then there should be a rationale for the change.

39. Other SD Sections to Ponder • Contraception • Study Drug/Agent • protocol specified • non-specified • Concomitant Medications • Toxicities • Questionnaires

40. Contraception – revised • Updated to reflect the changes in the revised TRP policy (to be released August 2002), “Guidance for Selecting and Modifying the Appropriate Protocol Eligibility Criteria Template for Pregnancy Prevention”. • Addresses reproductive potential of children/ adolescents. • Must not participate in a conception process…and if participating in sexual activity that could result in pregnancy, the study volunteer/partner must use…

41. Concomitant Meds: Non-Study • All Non-Study specified • Suggestions: Include • non-Rx. Drugs (aspirin) • vitamins • illegal drugs • herbals

42. Study Drug/Agent • Dispensed only by written order of Investigator of Record or licensed practitioner responsible to IoR • Recorded in research record

43. Study Drug/Agent - revised • Protocol Specified • distributed by NIAID’s distribution center • specifically required by protocol • EXCEPT if the study is designed to evaluate subjects already receiving specified drugs as part of their routine medical care before study entry. • risks identified in the IC • Protocol will specify AE/SAE reporting

44. Study Drug/Agent • Non-Specified • agent used to address study’s primary therapeutic objective or other study objectives • types or classes of drugs • not specified by name • Risks do not need to be identified specifically • Protocol will specify AE/SAE reporting requirements

45. Toxicities: grading – revised • ALL toxicities and signs/symptoms, including those reported by the subject, must be recorded in the research record and assessed for clinical significance: • Numerical grade or written description that corresponds to the toxicity table. • Exceptions for abnormal labs & non-reportable AEs that are not clinically significant: • Grade is NOT required. • Assessment of event IS required. • Staff must assess and grade event if it was originally assessed by non-study staff. • Relationship to study agent only if it is a reportable SAE. • Alternate etiology if “not related” to study agent.

46. Questionnaires - revised • Retain completed form • Except if site staff are blinded to the completed questionnaire as per the protocol.

47. Internet Sites

48. Internet Sites • Regulations • Code of Federal Regulations (CFR) • http://www.access.gpo.gov/nara/cfr/index.html • DHHS — Protection of Human Subjects, 45CRF46 • Title 45: Public Welfare • Part 46: Protection of Human Subjects • FDA — Protection of Human Subjects, 21CFR50 • Title 21: Food and Drugs • Part 50: Protection of Human Subjects • FDA — Institutional Review Boards, 21CFR56 • Title 21: Food and Drugs • Part 56: Institutional Review Boards

49. Internet Sites continued… • Regulations • FDA — Investigational New Drugs, 21CFR312 • Title 21: Food and Drugs • Part 312: Investigational New Drug Application • FDA — Electronic Records, 21CFR11 • Title 21: Food and Drugs • Part 11: Electronic Records; Electronic Signatures • FDA — Financial Disclosure, 21CFR54 • Title 21: Food and Drugs • Part 54: Financial Disclosure By Clinical Investigators • FDA Financial Disclosure Forms FDA 3454 & 3455 • http://www.fda.gov/opacom/morechoices/fdaforms/cder.html

50. Internet Sites continued… • Guidances • FDA • http://www.fda.gov • Good Clinical Practice • http://www.fda.gov/cder/guidance/index.htm • Select “ICH” (from list on left) • “Efficacy” (scroll down on right) • “E6: Good Clinical Practice” • Computerized Systems Used in Clinical Trials • http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.pdf • Financial Disclosure By Clinical Investigators • http://www.fda.gov/oc/guidance/financialdis.html