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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 1
Principles
 Ensure data quality
 Create an audit trail
 Verify all data
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 2
Local Requirements
Always refer to local, state, institution, and
IRB/IEC policies and procedures.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 3
Essential Document SOP
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 4
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 5
IRB Approvals – revised
3. 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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 6
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 7
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 8
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 9
Signature Key
 Key must include:




initials
printed signature
legal signature (first and last name)
credentials (if appropriate)
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 10
Source Documentation SOP
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 11
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
DHHS/NIH/NIAID/DAIDS

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

Laboratory reports
Medication records
Prescriptions
Radiology reports
SOP Training July 27, 2002 Slide # 12
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 13
Informed Consent
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 14
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.
3. Written consent required for screening unless
IRB waives requirement.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 15
Screening…..
4. Either IRB approved generic screening consent or
protocol specific consent is acceptable.
 Screening consent must be signed before
screening begins.
5. 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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 16
Screening
Find out how HIPPA is going to impact
screening activities at your site!!
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 17
Special Populations

Refer to 45 CFR 46 for special requirements of
obtaining informed consent of special
populations in research.
1. Pregnant women, fetuses, and neonates
(subpart B)
2. Prisoners (subpart C)
3. Children (subpart D)
 Includes adolescents
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 18
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 19
Requirements
1. 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.
4. All consent forms for new protocols and
amendments must be approved by DAIDS.
5. Protocol-specific consent must be obtained prior
to randomizing/enrolling subject.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 20
Signatures
1. 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.
5. Must be dated by each person signing the form
(It is NOT acceptable for research staff to complete the
date for another signer).
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 21
Signatures
1. 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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 22
Signatures
•
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
SOP Training July 27, 2002 Slide # 23
Case Report Forms (CRFs)
as
Source Documents (SDs)
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 24
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 25
Copies: certified
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 26
Copies: Certified – revised
It is a suggestion,
NOT
a requirement to certify copies of
source documentation.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 27
Source Document SOP
What’s the difference?



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Chart Note
Flow Sheets
Medical Records
Research Record
Source Document
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 28
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 29
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 30
Medical Records
 At institutions with primary care facilities
 must be accessible to monitor
 if missing, staff notes efforts to locate them
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 31
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 32
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
SOP Training July 27, 2002 Slide # 33
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 34
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 35
Source Document
 Original or certified copy
 Includes:
 Medical Record
 Primary Care office chart
 Clinic Chart
 Flow sheets, medical
records, Rx, EKG
 CRFs used as SD
 Research record
 Sites must provide direct access to all requested,
relevant documentation
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 36
Source Document
No documentation for
protocol required data
=
Inadequate
Source documentation
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 37
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 38
Other SD Sections to Ponder
 Contraception
 Study Drug/Agent
 protocol specified
 non-specified
 Concomitant Medications
 Toxicities
 Questionnaires
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 39
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
SOP Training July 27, 2002 Slide # 40
Concomitant Meds: Non-Study
 All Non-Study specified
 Suggestions: Include




non-Rx. Drugs (aspirin)
vitamins
illegal drugs
herbals
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 41
Study Drug/Agent
 Dispensed only by written order of Investigator
of Record or licensed practitioner responsible to
IoR
 Recorded in research record
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 42
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 43
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 44
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.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 45
Questionnaires - revised
 Retain completed form
 Except if site staff are blinded to the completed
questionnaire as per the protocol.
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 46
Internet Sites
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 47
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 48
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 49
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
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 50
Internet Sites continued…

Guidances
 Regulatory information
 http://www.fda.gov/cder/regulatory/default.htm
 Information Sheets
 http://www.fda.gov/oc/ohrt/irbs/default.htm
 Information for Health Professionals
 http://www.fda.gov/oc/oha/
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 51
Internet Sites continued…
 Guidances
 OHRP
 http://ohrp.osophs.dhhs.gov/
– Workshop schedule
– Educational materials
– Compliance Information
 IRB Guidebook
 http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm
 Guidance materials
 http://ohrp.osophs.dhhs.gov/g-topics.htm
 Policy information
 http://ohrp.osophs.dhhs.gov/polasur.htm
– Regulations
– Informed consent
– Assurances
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 52
Internet Sites continued…
 Guidances and Information
 NIH
 http://www.nih.gov
 Grants Policy and Guidance
 http://grants.nih.gov/grants/policy/policy.htm
 Policy: Education in the Protection of Human
Research Subjects
 http://grants.nih.gov/grants/guide/notice-files/NOTOD-00-039.html
 Frequently Asked Questions:
http://grants.nih.gov/grants/policy/hs_educ_faq.htm
 Bioethics Resources on the Web
 http:// www.nih.gov/sigs/bioethics/
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 53
Internet Sites continued…

Guidances and Information
 NIAID
 http://www.niaid.nih.gov
 DAIDS
 http://www.niaid.nih.gov/daids/
 Regulatory Operations Center
 http://roc.s-3.com/
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 54
Internet Sites continued…
 Professional Organizations (a few examples)
 Associates of Clinical Research Professionals
 http://www.acrpnet.org/index.html
 Barnett International
 http://www.barnettinternational.com/
 Center for Clinical Research Practice:
 http://www.ccrp.com
 Drug Information Association
 http://www.diahome.org/
 Institute for International Research
 http://www.iir-ny.com
 Pharmaceutical Training Institute
 http://www.pharmatraining.org
 RAN Institute, Inc.
 http://www.raninstitute.com/
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 55
Contact
Margaret Matula
e-mail: mm154j@nih.gov
phone: 301-402-2302
DHHS/NIH/NIAID/DAIDS
SOP Training July 27, 2002 Slide # 56