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

Principles Ensure data quality Create an audit trail Verify all data These are principles behind the 2 SOPs. DHHS/NIH/NIAID/DAIDS

Local Requirements Always refer to local, state, institution, and IRB/IEC policies and procedures. Follow local SOPs if they’re more stringent. DHHS/NIH/NIAID/DAIDS

Essential Document SOP DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

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 DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

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

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. DHHS/NIH/NIAID/DAIDS

Signature Key Key must include: initials printed signature legal signature (first and last name) credentials (if appropriate) DHHS/NIH/NIAID/DAIDS

Source Documentation SOP DHHS/NIH/NIAID/DAIDS

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 DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

Informed Consent DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

Screening Find out how HIPPA is going to impact screening activities at your site!! DHHS/NIH/NIAID/DAIDS

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

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 FDA regulation = 21CFR50.20 OHRP regulation = 45CRF46.116 DHHS/NIH/NIAID/DAIDS

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 DHHS/NIH/NIAID/DAIDS

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). DHHS/NIH/NIAID/DAIDS

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

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. DHHS/NIH/NIAID/DAIDS

Case Report Forms (CRFs) as Source Documents (SDs) DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

Copies: certified DHHS/NIH/NIAID/DAIDS

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

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”. DHHS/NIH/NIAID/DAIDS

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

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

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

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

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

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

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

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 DHHS/NIH/NIAID/DAIDS

No documentation for protocol required data Source Document No documentation for protocol required data = Inadequate Source documentation DHHS/NIH/NIAID/DAIDS

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

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

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

Concomitant Meds: Non-Study All Non-Study specified Suggestions: Include non-Rx. Drugs (aspirin) vitamins illegal drugs herbals DHHS/NIH/NIAID/DAIDS

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

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

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 DHHS/NIH/NIAID/DAIDS

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. DHHS/NIH/NIAID/DAIDS

Questionnaires - revised Retain completed form Except if site staff are blinded to the completed questionnaire as per the protocol. DHHS/NIH/NIAID/DAIDS

Internet Sites DHHS/NIH/NIAID/DAIDS

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 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

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 http://www.fda.gov/opacom/morechoices/fdaforms/cder.html 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

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 Regulatory guidances— Computerized Systems used in Clinical Trials Financial Disclosure Information Sheets = http://www.fda.gov/oc/ohrt/irbs/default.htm DHHS/NIH/NIAID/DAIDS

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/ Regulatory guidances— Computerized Systems used in Clinical Trials Financial Disclosure Information Sheets = http://www.fda.gov/oc/ohrt/irbs/default.htm DHHS/NIH/NIAID/DAIDS

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 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) --http://ohrp.osophs.dhhs.gov/irbasur.htm Guidance materials (listed by topic) http://ohrp.osophs.dhhs.gov/g-topics.htm DHHS/NIH/NIAID/DAIDS

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/NOT-OD-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/ Bioethics Resources on the Web (with links to resources): DHHS/NIH/NIAID/DAIDS

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/ Bioethics Resources on the Web (with links to resources): DHHS/NIH/NIAID/DAIDS

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/ 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

Contact Margaret Matula e-mail: mm154j@nih.gov phone: 301-402-2302 DHHS/NIH/NIAID/DAIDS