1. Essential Documents & Source Documentation SOPs
Margaret Matula, R.N., M.G.A.
Nurse Consultant
Clinical Research Management Branch
TRP/DAIDS/NIAID/NIH
phone:
DHHS/NIH/NIAID/DAIDS

2. Principles Ensure data quality Create an audit trail Verify all data
These are principles behind the 2 SOPs.
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3. Local Requirements
Always refer to local, state, institution, and IRB/IEC policies and procedures.
Follow local SOPs if they’re more stringent.
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4. Essential Document SOP
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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.
Essential docs individually and collectively permit evaluation.
The SOP on Essential Documents indicates:
DAIDS’ RECOMMENDATION for where the document should be filed.
A reference for the requirement in case you want to look up more info about it.
I want to stress that these documents are the ones usually audited by the sponsor and inspected by the regulatory authorities as part of the process to confirm the validity of the trial conduct and the integrity of data collected.
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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
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7. Laboratory – revised CLIA Certification of Compliance
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
This section is one that will be revised.
There are 4 numbered items—this slide only shows # 1 & # 4.
Last 2 bullets under #1 are from the FDA GCP section on essential documents, we will be revising to say these apply to international labs where CLIA doesn’t apply.
Many of the research labs (esp peds) are using their results to guide treatment decisions so they are exploring CLIA certification.
All labs in the US must abide by regs pertaining to CLIA.
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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
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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.
Serves 2 purposes.
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10. Signature Key Key must include: initials printed signature
legal signature (first and last name)
credentials (if appropriate)
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11. Source Documentation SOP
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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
Source Documentation is a very simply worded definition that covers everything that is needed to verify a subject’s participation in the trial and the data collected!
All info necessary for the reconstruction and evaluation of the trial:
Clinical findings
Observations
Other activities in a clinical trial
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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
Upon request of a monitor, the IRB, the FDA or regulatory authority, the investigator/institution must make available for direct access all requested documentation that may be relevant to the subject’s trial participation.
This includes CRFs and medical records.
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14. Informed Consent
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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.
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16. Screening….. Screening consent must be signed before screening begins.
4. Either IRB approved generic screening consent or protocol specific consent is acceptable.
Screening consent must be signed before screening begins.
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.
7. Maintain a list of subjects screened for a protocol.
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17. Screening
Find out how HIPPA is going to impact screening activities at your site!!
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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
Pregnant women can only be included in research if:
Mother & Father are competent and give their consent
Exceptions to father’s consent:
If research is to meet the health needs of mother
Father’s identity or whereabouts cannot be ascertained
He is not reasonably available
Pregnancy resulted from rape or incest
Prisoners
Approval by OHRP for IRB’s ability to review for prisoner participation
Requires additional IRB membership to include at least one member who is either a prisoner, or a prisoner representative with appropriate background and experience.
Additional duties of IRB are also included, for types of research permitted, as well as numerous safeguards to prevent any semblance of coercion (eg parole contingent on participation)
Children
Assent required (age determined by IRB)
Assent is child’s affirmative agreement to participate in protocol.
IRB determines documentation requirements.
Consent of parents
IRB may determine that one parent’s consent is sufficient, but only if minimal risk is involved, or if there is direct benefit to the child.
If >minimal risk, or if no direct benefit, both parents’ consent required
Adolescents
IRB may waive parental consent requirement if allowed by state law for adolescents
IRB decision must be filed in site regulatory files (should also address age for adolescent consent)
DHHS/NIH/NIAID/DAIDS

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:
FDA guidance:
FDA regulation = 21CFR50.20
OHRP regulation = 45CRF46.116
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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.
Except if IRB has waived requirement in accordance with regs
Such waiver must be in site regulatory files
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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).
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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.
·    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:
1.  Obtain a new, signed consent with the legal name.
2.  Notify the local IRB/IEC. Retain IRB/IEC correspondence on this issue in their files.
3.  Document the events in the research record and the actions taken by the site.
4.  Ensure that there is documentation linking the two names.
Ø  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).
5.  Follow local institutional/IRB policy regarding continued use of the alias.
·    If a subject is not able to write or sign his/her name in the form of a traditional “signature” as indicated above:
1.  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”.
2.  Also refer to the bullet on illiterate persons in this section.
DHHS/NIH/NIAID/DAIDS

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.
·    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:
1.  Obtain a new, signed consent with the legal name.
2.  Notify the local IRB/IEC. Retain IRB/IEC correspondence on this issue in their files.
3.  Document the events in the research record and the actions taken by the site.
4.  Ensure that there is documentation linking the two names.
Ø  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).
5.  Follow local institutional/IRB policy regarding continued use of the alias.
·    If a subject is not able to write or sign his/her name in the form of a traditional “signature” as indicated above:
1.  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”.
2.  Also refer to the bullet on illiterate persons in this section.
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24. Case Report Forms (CRFs) as Source Documents (SDs)
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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.
Maintain a list of the CRFs they are using as source documentation—to ensure consistency at the site & to indicate to monitors & auditors the CRFs being used as SD.
Person completing the CRF has to sign/initial & date it as they would any other SD so that there is a clear audit trail of who completed the documentation.
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26. Copies: certified
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27. Copies: Certified – revised
It is a suggestion,
NOT
a requirement to certify copies of source documentation.
This statement will move from the “requirement” section to the “suggestions” section.
DHHS/NIH/NIAID/DAIDS

28. Chart Note Flow Sheets Medical Records Research Record Source Document
Source Document SOP
What’s the difference?
Chart Note
Flow Sheets
Medical Records
Research Record
Source Document
How they relate, from the more narrow to the broad, all encompassing “source document”.
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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
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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
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31. Medical Records At institutions with primary care facilities
must be accessible to monitor
if missing, staff notes efforts to locate them
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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.
Retrieval of medical records to verify AEs/medical interventions is driven by the need to gather sufficient information for adequate clinical assessment of the subjects medical condition, rather than the need to provide such records for monitoring purposes.
What is reportable as an SAE is determined by the SAE Reporting Manual and may include toxicities.
Basically, we suggest that you get them all; however, you are required to get those that support SAEs.
DHHS/NIH/NIAID/DAIDS

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.
DHHS/NIH/NIAID/DAIDS

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.
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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.
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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
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37. No documentation for protocol required data
Source Document
No documentation for protocol required data =
Inadequate
Source documentation
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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.
Remember, you are providing an audit trail—was there a legit reason for the change?
DHHS/NIH/NIAID/DAIDS

39. Other SD Sections to Ponder
Contraception
Study Drug/Agent
protocol specified
non-specified
Concomitant Medications
Toxicities
Questionnaires
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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…
DHHS/NIH/NIAID/DAIDS

41. Concomitant Meds: Non-Study
All Non-Study specified
Suggestions: Include
non-Rx. Drugs (aspirin)
vitamins
illegal drugs
herbals
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42. Study Drug/Agent
Dispensed only by written order of Investigator of Record or licensed practitioner responsible to IoR
Recorded in research record
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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
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44. Study Drug/Agent Non-Specified types or classes of drugs
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
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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.
Grade or description that corresponds to toxicity table.
Abnormal labs exception applies if lab is listed in toxicity table.
Note in research record, initial & date report.
Purpose: Verify symptoms/results have been assessed.
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46. Questionnaires - revised
Retain completed form
Except if site staff are blinded to the completed questionnaire as per the protocol.
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47. Internet Sites
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48. Internet Sites Regulations Code of Federal Regulations (CFR)
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
Part 56: Institutional Review Boards
On each of the following slides, the 1st link will also get you to all of the others that I have also listed below.
DHHS/NIH/NIAID/DAIDS

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
Part 11: Electronic Records; Electronic Signatures
FDA — Financial Disclosure, 21CFR54
Part 54: Financial Disclosure By Clinical Investigators
FDA Financial Disclosure Forms FDA 3454 & 3455
On each of the following slides, the 1st link will also get you to all of the others that I have also listed below.
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50. Internet Sites continued…
Guidances
FDA
Good Clinical Practice
Select “ICH” (from list on left)
“Efficacy” (scroll down on right)
“E6: Good Clinical Practice”
Computerized Systems Used in Clinical Trials
Financial Disclosure By Clinical Investigators
Regulatory guidances—
Computerized Systems used in Clinical Trials
Financial Disclosure
Information Sheets =
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51. Internet Sites continued…
Guidances
Regulatory information
Information Sheets
Information for Health Professionals
Regulatory guidances—
Computerized Systems used in Clinical Trials
Financial Disclosure
Information Sheets =
DHHS/NIH/NIAID/DAIDS

52. Internet Sites continued…
Guidances
OHRP
Workshop schedule
Educational materials
Compliance Information
IRB Guidebook
Guidance materials
Policy information
Regulations
Informed consent
Assurances
If you want to learn about what OHRP requires of IRBs--this is it!
Procedures for Registering Institutional Review Boards and Filing Federalwide Assurances of Protection for Human Subjects (FWAs) --
Guidance materials (listed by topic)
DHHS/NIH/NIAID/DAIDS

53. Internet Sites continued…
Guidances and Information
NIH
Grants Policy and Guidance
Policy: Education in the Protection of Human Research Subjects
Frequently Asked Questions:
Bioethics Resources on the Web
Bioethics Resources on the Web (with links to resources):
DHHS/NIH/NIAID/DAIDS

54. Internet Sites continued…
Guidances and Information
NIAID
DAIDS
Regulatory Operations Center
Bioethics Resources on the Web (with links to resources):
DHHS/NIH/NIAID/DAIDS

55. Internet Sites continued…
Professional Organizations (a few examples)
Associates of Clinical Research Professionals
Barnett International
Center for Clinical Research Practice:
Drug Information Association
Institute for International Research
Pharmaceutical Training Institute
RAN Institute, Inc.
Here are a few examples of websites for professional organizations that offer courses:
Drug Information Association:
Associates of Clinical Research Professionals:
Barnett International:
Center for Clinical Research Practice:
Institute for International Research:
RAN Institute, Inc
DHHS/NIH/NIAID/DAIDS

56. Contact Margaret Matula e-mail: mm154j@nih.gov phone: 301-402-2302
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