sop training july 27, 2002 slide # 1 dhhs/nih/niaid/daids essential documents & source...

DHHS/NIH/NIAID/DAIDS SOP Training July 27, 2002 Slide # 1

Essential Documents &

Source Documentation SOPs

Margaret Matula, R.N., M.G.A. Nurse Consultant

Clinical Research Management BranchTRP/DAIDS/NIAID/NIH

e-mail: [email protected]: 301- 402- 2302


Principles

Ensure data quality

Create an audit trail

Verify all data


Local Requirements

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


Essential Document SOP


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.


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 IND Safety Reports, Safety Memos, & Safety

AlertsAlerts Investigator’s BrochuresInvestigator’s Brochures


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 StatesResults of an established quality control and/or

external quality assessment program

Other validation


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


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.


Signature Key

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


Source Documentation SOP


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.

Clinic chart Medical record Office notes Flow sheets

Laboratory reports Medication records Prescriptions Radiology reports

Includes but is not limited to:


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


Informed Consent


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.


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.


Screening

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


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


Other Special Populations…..

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

Non-English Speaking

Information given to subject must be in language they understand—


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.


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).


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.


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.


Case Report Forms (CRFs) as

Source Documents (SDs)


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.


Copies: certified


Copies: Certified – revised

It is a suggestion, NOT

a requirement to certify copies of source documentation.


Source Document SOP

Chart Note Flow Sheets Medical Records Research Record Source Document

What’s the difference?


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


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


Medical Records

At institutions with primary care facilities

must be accessible to monitor

if missing, staff notes efforts to locate them


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.


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.


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.


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.


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


Source Document

No documentation for

protocol required data

=

Inadequate

Source documentation


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.


Other SD Sections to Ponder

Contraception

Study Drug/Agent

protocol specified

non-specified

Concomitant Medications

Toxicities

Questionnaires


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…


Concomitant Meds: Non-Study

All Non-Study specified Suggestions: Include

non-Rx. Drugs (aspirin) vitamins illegal drugs herbals


Study Drug/Agent

Dispensed only by written order of Investigator of Record or licensed practitioner responsible to IoR

Recorded in research record


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


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


Toxicities: grading – revised

ALL toxicities and signs/symptoms, including those reported by the subject, must be recorded in the research record and assessed for assessed for clinical significanceclinical significance:

Numerical grade or written description that corresponds to the toxicity table.

Exceptions for abnormal labs & non-reportable AEs that are Exceptions for abnormal labs & non-reportable AEs that are not clinically significant:not clinically significant:

Grade is NOT required.Grade is NOT required.

Assessment of event IS 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.


Questionnaires - revised

Retain completed form

Except if site staff are blinded to the completed questionnaire as per the protocol.


Internet Sites


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


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


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


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/


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


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/


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/


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/


Contact

Margaret Matula

e-mail: [email protected]

phone: 301-402-2302