Common Regulatory Documents

Document

Purpose & Tips

File

Regulatory
Reference

Monitoring Reports, Log, and Correspondence

(See #1 of the Regulatory Binder)

The reports document the findings of the monitor, usually a written report to the sponsor after each site visit or other trial-related communication.

A monitoring log can document visits to the site, and may be used to track all outside visitors who review the study. This can also be useful to document all outside persons who have had access to confidential study materials and when.

If a visit occurs over more than one day, each day can be recorded on a separate line in the log.

The log may note how the visit occurred since monitoring visits can include phone contact, email, or other types of communication with the site where trial-specific issues are discussed.

The log can document whether the monitor provided a report to the site, and whether the report was provided to the IRB.

Monitoring reports are considered an essential document per GCP. Only the trial initiation monitoring report is listed as an investigator/ institution file.

In the Regulatory Binder at the site

(Reports may only be in the sponsor file)

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

1.38

1.39

4.1.4

5.18 (5.18.6)

8.2.19 & 8.2.20

8.3.10

8.4.5

21 CFR 312.56 21 CFR 812.46

FDA’s “Guideline for the Monitoring of Clinical Investigations”

Oversight of Clinical

Investigations –

A Risk-Based Approach to

Monitoring

Delegation Log

(See #2 of the Regulatory Binder)

The overall responsibility for a clinical trial rests with the Principal Investigator. The Principal Investigator can delegate specific responsibilities to various members within the team. These responsibilities should be formally assigned.

Any individual to whom a task is delegated should be qualified to perform the delegated task. A protocol may specify the qualifications of the individuals who are to perform certain protocol-required tasks, in which case the protocol must be followed even if individuals with different qualifications may otherwise be permitted to perform the task.*

A delegation log can help keep track of the responsibilities of the various team members.

An investigator should maintain separate lists for each study conducted by the investigator*, so delegation logs should be study-specific rather than maintaining a central one for all of a PI’s studies.

The list or log should include the start and end dates of a team member’s involvement in the study*, or the start and end dates of their specific responsibilities if they change during the study.

The regulatory binder should also identify the training that individuals have received that qualifies them to perform delegated tasks.* The delegation log can refer to other documents (like a CV) that identify qualifications.

In the Regulatory Binder at the site

ICH Guidance: E6 GCP Sections:

4.3.1

4.1.5

5.18.4h

*FDA Guidance for Industry: Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects

Section III, A, 1

Signature Log

(See #3 of the Regulatory Binder)

For GCP, to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs.

Capturing the original signature and initials of all staff members prior to start on the study may help authenticate or verify data entry if questioned, based on handwriting/signature.

A signature log can provide an updated reference of research staff, past and present, which can be especially helpful for studies that are long in duration, have large staff number, and/or have staff turnover during the study.

Considered an essential document per GCP

In the Regulatory Binder at the site

ICH Guidance: E6 GCP Sections:

8.3.24

Study Personnel Education

(See #4 of the Regulatory Binder)

There should be adequate training for all staff participating in the conduct of a study, including any new staff members that start after the study has begun.

Staff should be familiar with the purpose of the study and the protocol, have an adequate understanding of the specific details of the protocol and attributes of the investigational product needed to perform their assigned tasks, be aware of regulatory requirements and acceptable standards for the conduct of clinical trials and the protection of human subjects, be competent to perform or have been trained to perform the tasks they are delegated, and be informed of any pertinent changes during the conduct of the trial and receive additional training as appropriate.*

If the sponsor provides training for investigators in the conduct of the study, the investigator should ensure that staff receive the sponsor’s training, or any information (e.g., training materials) from that training that is pertinent to the staff’s role in the study.*

Certification that one has completed training in human subject protection in research is required of all faculty, investigators, study coordinators and other individuals directly involved in human subject research. This means anyone working directly with human research participants, data, or tissue that can link back to individual research participants . Typically this includes all individuals listed on a research protocol, including those whose work is limited to chart/medical record reviews, database inquiries, discarded biological specimens, and data analysis or statistical support if they can link back the data.

HIPAA training specific for human subject research is also required.

Documentation of study-related training is a record of training provided, e.g. protocol training, investigational product training, or other study-specific training of staff.

This would include a site initiation visit (SIV) attendance log.

Include other applicable education such as Good Clinical Practice training and Dangerous Goods Training.

Keep all training records from the start of the study, even those that have expired, to maintain an audit trail.

In the Regulatory Binder at the site.

Submit proof of human subject protection training and HIPAA training to the IRB, and update every 3 years.

ICH Guidance: E6 GCP Sections:

2.8

4.1.1 – 4.1.3

4.2.4

5.23.4

8.2.20

HHS Investigator Responsibilities

FAQs;

Terms of FWA;

*FDA guidance, “Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects

Section III, A, 2

Curriculum Vitae, medical licenses, professional certifications

(See #5 of the Regulatory Binder)

1.Maintain the CV and/or other relevant documents indicating the qualifications and eligibility of investigators and other key personnel to conduct a trial and/or to provide medical supervision of subjects

2. Valid licenses & certifications for all professional study staff (e.g., medical or nursing license)

3. Current professional certifications that verify staff eligibility to perform clinical procedures (e.g. phlebotomy, vital signs, ECG)

4. Available for all investigators and other members of the study team, including any new staff members that start after the study has begun.

5. Monitor expiration dates so those nearing expiration can be promptly updated.

6. Update/revise CVs as needed with significant changes such as affiliation, education, and responsibilities. It is recommended to sign, date, and update CVs every 2 years to verify that the information is accurate and current.

7. For IND studies, maintain appropriate documents for the investigator listed in section #1 of the FDA 1572 Form, as well as those individuals listed in section #6.

8. Keep all CVs, licenses, and certifications from the start of the study, even those that have expired or have been replaced, to maintain an audit trail.

9.If CVs are filed collectively for the department, write a signed and dated note-to-file indicating the location.

10. If CVs are maintained electronically, include the “date prepared” on them.

Considered an essential document per GCP

In the Regulatory Binder at the site

Submit the CV of the PI to the IRB.

ICH Guidance: E6 GCP Sections:

2.7

3.1.2

4.1.1

4.3.1

8.2.10

8.3.5

Investigator Statements/

Agreements

(See #5 of the Regulatory Binder)

A Statement of Investigator, Form FDA 1572, is an agreement signed by the

investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic. It is used for clinical investigations being conducted under an investigational new drug application (IND).

The list of individuals named on the1572 should be consistent with the protocol submitted to the IRB.

The site should maintain a signed investigator agreement for device studies.

In the Regulatory Binder at the site

Submit new/updated 1572s to the IRB to verify the list of individuals named

21 CFR 312

21 CFR 312.53c

21 CFR 812.43c

Information Sheet

Guidance for

Sponsors, Clinical

Investigators, and

IRBs

Frequently Asked Questions â€“

Statement of Investigator

(Form FDA 1572)

Financial Disclosure

(see #5 of the Regulatory Binder)

1. Disclosure statement to:

Certify that there is no financial interest or
Disclose specific financial interests

2. Proper procedure for institutional disclosure forms should be followed per IRB and institutional policies. Generally, a study-specific financial disclosure form is requested from each individual during the initial IRB application and at each continuing review.

3. For IND studies, maintain appropriate disclosure statements for the investigator listed in section #1 of the FDA 1572 Form, as well as those individuals listed in section #6. Make sure the list of individuals named on the1572 is consistent with the protocol submitted to the IRB so that disclosure information submitted to the sponsor and to the IRB are consistent.

4. For studies considered covered clinical studies by FDA, maintain signed and dated copies of all Forms FDA 3454 and 3455.

In the Regulatory Binder at the site

Submit institutional disclosure forms to IRB

21 CFR 54

21 CF 312

21 CFR 54.2(d) and 54.4

FDA

Guidance:

Financial

Disclosure by

Clinical

Investigators

Guidance for Clinical Investigators, Industry, and FDA Staff Financial Disclosure by Clinical Investigators

Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection

Financial Aspects of the Trial

Document the financial aspects of the trial and the financial agreement between the investigator/institution and the sponsor for the trial (may be part of the CTA)

Considered an essential document per GCP

In the Regulatory Binder at the site

ICH Guidance E6 GCP: Section

4.9.6

8.2.4

Public Registration of Research Studies

(See #6 of the Regulatory Binder)

All research studies that are applicable clinical trial must be registered at www.clinicaltrials.gov as per the International Committee of Medical Journal Editors (ICMJE), the FDA Amendment Act of 2007, and institutional policy.

Contact the Georgetown Protocol Registration System Administrator, Patricia Mazar at mazarp@georgetown.edu to set up a PRS user account.

Maintain the registration receipt for initial registration and for any updates.

For commercially funded, multi-center studies, public registration is typically handled by the study sponsor or CRO.

Incorporate the required language into the informed consent document for applicable clinical trials. The required language is included in the consent form templates provided by the GU IRB.

In the Regulatory Binder at the site

FDAAA; U.S. Public Law 110-85, Title VIII

42 U.S.C. § 282(j)(1)(A)

Fact Sheet:

Clinicaltrials.gov Fact Sheet

(also see 21 CFR § 50.25(c) for consent)

Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c)

Guidance for Sponsors, Investigators, and Institutional Review Boards

Screening, Enrollment, and Randomization Logs

(See #7 of the Regulatory Binder)

1. Document identification of subjects who entered pretrial screening

2. Document chronological enrollment of subjects by number

3. Screening and enrollment/randomization logs may be separate or combined

4. May include reasons for screen failures

5. An enrollment log may be useful to track the number of subjects enrolled and the rate of enrollment for continuing renewal with the IRB.

6. A log may keep track of the following information:

Number of subjects who provided consent
Number of subjects determined to be ineligible
Number of subjects currently active/on study
Number of subjects withdrawn at subject’s request
Number of subjects withdrawn at the request of the investigator
Number of subjects withdrawn due to adverse events/unanticipated problems
Number of subjects lost to follow-up
Number of subjects no longer participating for other reasons
Number of subjects who have completed the study

7. When reporting subject numbers to the IRB at continuing review, take into account how many subjects provided consent, even if they do not progress in the study. Check with the IRB if you have questions about how to report subject numbers.

8. If you need to enroll more subjects than initially expected, obtain IRB approval before enrolling the additional subjects.

9. If the study only collects data (e.g., charts) or samples from individuals, count these individuals in the enrollment numbers.

Note: If screening and enrollment information is entered into an electronic data capture (EDC) system, please include a memo explaining this process.

Screening and enrollment logs are considered essential documents per GCP. A master randomization list is considered an essential document per GCP, and may only be in the sponsor file.

In the screening files or protocol files at the site

Submit information about enrollment to the IRB at continuing review

ICH Guidance: E6 GCP Sections:

4.7

8.2.18

8.3.20

8.3.22

OHRP continuing review guidance

Office for Human Research Protections (OHRP)

FDA continuing review guidance

Guidance for IRBs, Clinical Investigators, and Sponsors

Subject Visits and Termination

(See #8 of the Regulatory Binder)

Study visits may be documented with detailed progress notes or with visit checklists that outline required study procedures and data points that must be captured for each visit.

Documentation of a Study visit may include the following information:

â–ª Date of visit and Subject ID

â–ª Subject’s current status

â–ª Changes in subject’s condition or diagnosis

â–ª Subject’s response to planned intervention

â–ª Unexpected Occurrences

â–ª Completion of required procedures or tests

â–ª Any concerns or questions of the subject/family

â–ª Information pertinent to subject/family comprehension

â–ª Documentation that consent was obtained prior to research procedures or that subject expressed a continuing agreement to participate

Progress notes, study visit checklists, or another method for documenting visits are useful in addition to documents like admission notes, history and physician records, x-rays, labs, emergency room notes, etc.

Include additional details in study visit documentation which may pertain to the subject’s mood, cooperation and any questions that were discussed during the visit. Study visit documentation can provide valuable data about the conduct and understanding of the study that CRFs and other types of source documents (x-rays, labs, etc.) cannot.

Progress notes and study visit checklists can be very useful during data analysis as questions arise. For example, if the documentation of the study visit indicates that the subject was rushed because of a transportation issue, it could help explain missing information (a potential protocol deviation).

Logs may be a useful addition to progress notes and study visit checklists.

A subject visit tracking log can track all enrolled subjects’ visits and keeps visits scheduled as per protocol. It can also note where to find additional information if a subject did not complete a test or completed a test on different date, if the subject ended the study early, etc.

A subject withdrawal/completion log can track whether subjects completed the study, withdrew, or were terminated early, and can collect additional information about withdrawals.

Per GCP, a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, but the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights.

A log can also indicate if the subject participated in the study termination visit (which may be specified in the protocol for safety reasons).

It can also track if any subjects were partial withdrawals. For instance, a subject may stop the investigational product because of side effects, but the investigator may ask to continue follow up research activities.

OHRP recommends that when seeking the informed consent of subjects, investigators explain whether already collected data about the subjects will be retained and analyzed even if the subjects choose to withdraw from the research.*

For HHS-conducted or â€“supported research that is not subject to FDA regulations or the HIPAA Privacy Rule, the investigator should inform subjects whether the investigator intends to either: (1) retain and analyze already collected data relating to the subject up to the time of subject withdrawal; or (2) honor a research subject’s request that the investigator destroy the subject’s data or that the investigator exclude the subject’s data from any analysis.*

The investigator should decide whether to allow this and how to handle it before the study begins, so it should be mentioned in the protocol and informed consent. A withdrawal tracking log could note whether an individual subject requested to have data destroyed or excluded.

Regulatory binder

ICH Guidance: E6 GCP Sections:

4.3.4

21 CFR 312.62(b)

*Guidance on Withdrawal of Subjects from: Data Retention and Other Related Issues: Guidance on Withdrawal of Subjects from: Data Retention and Other Related Issues

FDA Guidance: Data Retention When Subjects

Withdraw from FDA-Regulated

Clinical Trials

Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials

Subject Identification Code List

(See #9 of the Regulatory Binder)

1.Document that the investigator keeps a confidential list of names and contact information of all subjects allocated to the trial upon enrolling to reveal the identity of any subject.

2. After completion of the trial, allows investigator/institution to permit identification of all subjects enrolled in the trial in case follow up is required.

3. List needs to be kept in a confidential manner and for agreed upon time.

4. May not be keeping in regulatory binder but in separate, secure place as specified in the IRB application, accessible to members of the study team who need it, as specified in the IRB application.

5. It may also be used to note whether the subjects’ primary care providers were notified of study participation, which may be useful to include here in case of follow-up.

Considered an essential document per GCP

In the protocol file at the site

ICH Guidance: E6 GCP Sections:

1.58

2.11

4.3.3

8.3.21

8.4.3

Consent Form

(See #10 of the Regulatory Binder)

1. Obtain signed informed consent forms in accordance with the process described in the protocol. They must be dated prior to participation of each subject in a trial. If consent is obtained the same day that study procedures start, please note the time consent is obtained.

2. Changes to a consent form may be initiated by the study team, the sponsor, or the IRB. Any change to a consent form must be approved by the IRB before the revised consent form is signed by subjects. Each subject must sign a copy of the consent form with the IRB approval/expiration stamp.

3. Use the consent form templates provided by the GU IRB. These templates include the elements of consent outlined in the regulations, as well as language related to institutional policies. Check with the IRB if you have questions about merging the GU template with a sponsor provided template. Submit the sponsor consent template to the IRB.

4. Be aware of the GU template version date, and check with the IRB regarding template revisions. Incorporate any applicable template revisions into your consent document if appropriate for the study (usually if the study is still consenting subjects). This may be done at the time of continuing review, or as indicated by the IRB for the study.

5. Save all versions submitted and approved by the Institutional Review Board (IRB) in the regulatory binder. Have a method to indicate the current consent form for the study team.

6. Document revisions of the trial-related documents that take effect during

the trial; save any revisions to:

Informed consent
Any other written information provided to the subjects

7. Retain consents obtained for screening purposes even if the subject was not enrolled

in the study

8. Non-English speaking subjects must be consented in a language they can

understand.

9. Check with the IRB if you have questions about consent and vulnerable populations (e.g., obtaining consent from non-English speaking subjects, capacity to consent and legally authorized representatives, assent & consent from children and parents).

10. If you are updating a consent due to an adverse event reported to the IRB, remember to document the corresponding AE number(s).

11. Changes to any other written information provided to the subjects also must be approved by the IRB before presenting the information to the subjects. Save all versions submitted and approved by the IRB in the regulatory binder. Study visit documentation should indicate what documents were presented to subjects and the dates (e.g., instructions for use on study visit #1; revised instructions on study visit #5; article addressing outcome from earlier study on study visit #14)

A consent revision log can provide a reference for study staff to determine when changes were made to the consent form and may also assist in ensuring the proper version of the consent form is used during the consent process or when proposing new revisions of the consent form.

A log can document revisions made to the consent form, as well as track proposed revisions currently pending IRB review and approval. It may be particularly helpful when there are multiple consent forms in use for a study (e.g., substudy consents or consents for different populations), the research staff is large, or the study will enroll subjects over a long period of time.

A consent revision log may also be useful as quality assurance tool to ensure that all staff members can determine if a version of the consent form is out of date and which is the currently approved consent form (in conjunction with eRIC). It may also serve as a useful tool to inform staff members that an amendment requesting changes to the consent is pending IRB approval.

Create a log that documents the version/date, date submitted to the IRB, date approved by the IRB, expiration date and a brief description of the changes. It may be helpful to reference page numbers or the corresponding date of the amendment form submitted. The PI may date and initial the log to verify that the revised consent form should be used moving forward.

The subject or the subject’s legally authorized representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.

A log can also note whether the updated consent will be used to reconsent subjects, and if so, whether reconsent is requested by the PI, the sponsor, or the IRB. Make sure to check with the IRB and/or sponsor if you aren’t sure when to reconsent.

Considered an essential document per GCP

IRB approved copies in the Regulatory Binder at the site and signed original consents in the subject’s research record or the research Regulatory Binder at the site.

Submit to the IRB

45 CFR 46

21 CFR 50

21 CFR 56

ICH Guidance: E6 GCP Sections:

1.28

3.1.2

4.6.6

4.8

8.2.3

8.2.7

8.3.2

8.3.12

A Guide to Informed Consent – Information Sheet

Office for Human Research Protections (OHRP)

OHRP

Informed

Consent

Guidance

Information

HHS.gov Informed Consent

Tips on informed consent: HHS.gov Tips on Informed Consent

FDA.gov Informed Consent Process

46.116

45 CFR 46.117

Assent: 45 CFR 46, subpart D

Guidance for Institutional Review Boards and Clinical Investigators 1998 Update

FAQ Nos. 47

and 48

Protocol

(See #11 of the Regulatory Binder)

Any changes to the protocol as written in the IRB application or in the sponsor protocol must be submitted to and approved by the IRB prior to implementation.

Save all versions of the IRB application and sponsor protocol submitted and approved by the Institutional Review Board (IRB).

Considered an essential document per GCP

In the Regulatory Binder at the site

Submit to the IRB

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

1.44

1.45

3.1.2

4.5.1(signatures)

5.23.1

8.2.2

8.3.2

21 CFR 312.30

21 CFR 812.35

Assurance Number

(See #12 of the Regulatory Binder)

The institution is responsible for obtaining and maintaining a current Health and Human Services (HHS) Federal Wide Assurance Number through the Office of Human Research Protection (OHRP).

This is available on the IRB website.

A copy of the current applicable FWA letter can be maintained in the regulatory binder.

The FWA letters for this institution indicate that the IRB is in compliance with the ICH GCP guidelines for IRBs.

In a Regulatory Binder at the site

A copy of the Assurance number must be on file with the sponsor

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

5.11.1

45 CFR 46

IRB

Correspondence

(See #13 of the Regulatory Binder)

1. Copies of all materials submitted to the IRB with dated proof of submission and IRB

approval (when appropriate) for the following:

Initial protocol submission (IRB application and sponsor protocol if applicable)
Advertisements and recruitment materials: document that recruitment measures are appropriate and not coercive
All versions of consent forms and assent forms
Any other written information to be provided to subjects (content and wording) to support their ability to give fully informed consent
All protocols and amendments
Annual reports and progress reports
Adverse event and unanticipated problem reports
Deviation reports
Investigator’s brochure, safety package inserts, device manuals
Protocol specific education material
Subject compensation
Any other documents reviewed by the IRB and/or receiving IRB approval
Correspondence related to contingent approvals or stipulations
Any other pertinent communications with the IRB

Changes should be tracked to compare differences between versions; keep all versions.

Ensure the study team is aware of requests or conditions of approval from the IRB (e.g. submitting a progress report 3 months after approval, not bolding the information about payment on any recruitment material).

Considered an essential document per GCP

In Regulatory Binder at the site

ICH Guidance: E6 GCP Sections:

3.1.4

3.1.2

3.3.8

4.10

4.4

5.11

5.17.1

8.2.3

8.2.7

8.3.2

8.3.3

8.3.19

8.4.7

45 CFR 46

21 CFR 50

21 CFR 56

21 CFR 312

21 CFR 812

21 CFR 812.150(b)(5)

21 CFR 312.33

IRB Membership Roster

(See #13 of the Regulatory Binder)

To document that the IRB is constituted in agreement with GCP.

There are currently five committees at Georgetown (Committees A-E). Check with the IRB office if you need to find out which committee or committees reviews the study.

Considered an essential document per GCP

In the Regulatory Binder at the site

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

3.2

3.4

5.11.1

8.2.8

21 CFR 312.66

21 CFR 812.60

21 CFR 56.106

21 CFR 56.107

45 CFR 46.501

(registration)

45 CFR 46.107

Final Closeout Reports

#13/#15

Final report by investigator is sent to the IRB where required and, where applicable, to the sponsor and to the regulatory authorities, to document completion of the trial.

May include the following information:

Disposition of the subjects
Location of the research records
Disposition of the specimens
Disposition of the study drugs
Other information as required by the institution or local IRB (e.g., number of patients screened, number enrolled, serious adverse experiences)

If you are still communicating with research subjects after completion of the trial, for instance, providing information about the study results, check with the IRB about approval of these communications and how they factor in to the closeout process.

Considered an essential document per GCP

In the Regulatory Binder at the site

ICH Guidance: E6 GCP Sections

4.13

8.4.7

Investigator’s Brochure (IB) and Safety Package Inserts

(See #14 of the Regulatory Binder)

1. Document that relevant and current scientific information about the investigational

product has been provided to the investigator

2. Include updates to document that investigator is informed in a timely manner of

relevant information as it becomes available

3. Keep a copy on file for EACH study medication or device used within the protocol

4. Include the following:

The most recent version
Addendum
Safety letters

5. Investigational devices may require documentation of the risk assessment to evaluate whether the device study is significant risk or nonsignificant risk.

Considered an essential document per GCP

In the Regulatory Binder at the site and in the pharmacy

Submit to the IRB

ICH Guidance:

E6 GCP Sections:

1.3.6

3.1.2

8.2.1

8.3.1

21 CFR 312.55 (sponsor)

Significant risk and nonsignificant risk devices:

Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors

Protocol Deviations/

Protocol Exceptions/

Violations

(See #16 of the Regulatory Binder)

Maintain records of all protocol deviations, their resolution, and IRB reporting status.

Protocol deviations related to individual participants may be included in the participants’ study record, but there may also be a protocol deviation log where all deviations are noted for the study as a whole.

Keep exceptions granted by the sponsor in the participant study record.

Communications regarding protocol violations are considered an essential document per GCP

A log can be kept in the Regulatory Binder at the site

Information about specific deviations should be kept in the participant’s individual study record

Report major deviations to the IRB when they occur; report minor deviations to the IRB at continuing review

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

3.3.7

4.5

8.3.11

21 CFR 312.66

21 CFR 312.53(c)(1)(vii)

Adverse Events (AE) and Unanticipated Problems

(See #17 of the Regulatory Binder)

1. Notification by originating investigator to sponsor of adverse events, related

reports, and other safety information

2. Notification by sponsor to investigators of safety information

3. Notification by sponsor and/or investigator, where applicable, to regulatory authorities

and IRB of unexpected adverse events, unanticipated problems, and of other safety information

Considered an essential document per GCP

A log can be kept in the Regulatory Binder at the site

Information about specific AEs should be kept in the participant’s individual study record

ICH Guidance: E6 GCP Sections:

1.1

1.2

1.50

1.60

4.11

5.16.2 & 5.17

8.3.16

8.3.17 & 8.3.18

21 CFR 312.66

45CF 46

21CFR50

21CFR56

21CFR312

45 CFR 46.103(b)(5)

IND Safety Reports

(See #18 of the Regulatory Binder)

Sponsors are specifically required to provide written IND safety reports to all participating investigators (and FDA).

Sponsors may instruct the investigators to submit IND safety reports to the IRB.

IRBs are required by FDA and DHHS human subjects protection regulations to review “unanticipated problems involving risks to participants or others.”

Different interpretations of the regulations, as well as the different terminology, can make it difficult to assess when to generate IND safety reports and when to submit IND safety reports to the IRB.

Check with the IRB if you aren’t certain. A site investigator generally submits safety reports to the IRB in the following cases:

When the report meets the definition of an unanticipated problem (see policy); or
When the report triggers a sponsor-required change in the research protocol or consent form; or
When the sponsor indicates the safety information must be reviewed by the IRB to determine whether an amendment is required or whether currently enrolled subjects should be informed of the new information.

In the Regulatory Binder at the site

21 CFR 312.32

Safety Reporting Requirements for

INDs and BA/BE Studies

Guidance for Industry and Investigators Safety: Reporting Requirements for INDs and BA/BE Studies

Advertising/

Education/

Written

Materials

(See #19 of the Regulatory Binder)

1. Include any IRB approved advertisements, recruitment flyers, written educational, or other materials provided to study participants.

2. This documents that recruitment measures are appropriate and not coercive.

3. Maintain all revisions to the documents. Have a method to indicate the current documents in use for the study team.

4. Consider whether you need to change information in the protocol or consent form to accompany a new or revised document (e.g., if you create an ad for craigslist, make sure that’s mentioned as a recruitment method in the protocol; if you add a questionnaire for a study, make sure the consent tells participants that there is a questionnaire)

In the Regulatory Binder at the site

Submit to the IRB

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

3.1.2

8.2.3

Sample Tracking and Shipping

(See #20 of the Regulatory Binder)

To maintain a record of retained body fluids/tissue samples to document location and identification of retained samples if assays need to be repeated.

A log may list specimens collected, type of specimen, and the shipment information for each one. It can be used to update shipment information as specimens are shipped or received.

If any blood specimens, other body fluids and/or tissue samples are retained for long-term storage at the site/institution, document location and identification of the retained samples. (e.g., A laboratory data management or tracking system.)

A log may also track specimens retained for future use to confirm that consent was obtained, what subjects consented to if options (e.g., blood vs. urine; use for cancer vs. other uses; yes to genetic testing), if consent is withdrawn, and to track sharing and transferring of repository samples (e.g., collaborators, mode, dates sent and received).

A record of retained body fluids/tissue samples is considered an essential document per GCP

In the Regulatory Binder at the site.

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

8.3.25

OHRP guidance: Issues to consider in the research use of stored data or tissue

OHRP – Guidance on Research Involving Coded Private Information or Biological Specimens

Temperature Logs for Refrigerator/

Freezer

(See #21 of the Regulatory Binder)

Document compliance with the protocol, study procedures, and applicable regulatory requirements.

In the Regulatory Binder at the site.

ICH Guidance: E6 Good Clinical Practice (GCP)

Sections:

2.12

4.6.4

5.13.2

5.14.3

5.18.4c

Investigational Product/Study Drug Accountability

(See #22 of the Regulatory Binder)

The PI is responsible for the following with respect to investigational drugs/devices:

o Maintain records of investigational product delivery to the study site. Include dates, quantities received, batch/serial numbers, and expiration dates.

o Maintain an inventory of the investigational product at any site. Inventory control records should be updated, signed, and dated in a timely manner.

o Record/track use of the investigational product by each participant. Documentation should verify that dosing/device use was in accordance with the approved protocol. Maintain an accountability log that records when the participant(s) received the drugs/device and the specific dosage/device the participant(s) received.

o Return/dispose of unused investigational product as specified by the sponsor. Maintain documentation of return/disposal.

o Store the investigational product. The storage area should be locked/secure with access limited to approved study staff only. Drugs/devices should not be stored with standard clinical inventory.

This should be done in collaboration with the research pharmacy.

Considered essential documents per GCP

In the pharmacy records and the regulatory binder at the site

ICH Guidance: E6 GCP Sections:

4.6

5.13

5.14

8.2.14

8.2.15

8.2.16

8.3.8

8.3.9

8.3.23

8.4.1

8.4.2

21 CFR 312.57

21 CFR 312.62

21 CFR 812.140

Unblinding

(See #22 of the Regulatory Binder)

1. Decoding procedures for blinded trials to document how, in case of an emergency,

identity of blinded investigational product can be revealed without breaking the blind

for the remaining subjects’ treatments

2. Document any decoding that may have occurred at the site during the trial

Considered an essential document per GCP

In the protocol files at the site or in the pharmacy files and in the participant record

ICH Guidance: E6 GCP Sections:

1.10

4.7

8.2.17

8.4.6

Research Laboratory

(See #23 of the Regulatory Binder)

1. Document competence of facility to perform required tests, and support reliability of

results of medical/laboratory/technical procedures/tests:

Certification or Accreditation
Update when certifications expire or laboratory changes to document that tests remain adequate throughout the trial period
Established quality control and/or external quality assessment

2. Document normal values/ranges for medical/laboratory/technical procedures/tests

included in the protocol

3. Update documentation of normal values/ranges when they are revised during the trial

4. The reference ranges and certifications should be on file for the following listings:

Local or central laboratories that analyze specimens for the study
Any group central laboratory

Expired certifications should not be removed from the file

Considered an essential document per GCP

In the Regulatory Binder at the site

ICH Guidance: E6 GCP Sections

8.2.11

8.2.12

8.3.6

8.3.7

Correspondence/

Communications

(See #24 of the Regulatory Binder)

1. Document all relevant communications/correspondence other than site visits, for example:

Letters
Meeting notes
Notes or log of telephone calls with either subject or Sponsor
E-Mail messages

2. File subject specific communications with source documents in the subject’s

research record (e.g., communications about study results or medical care for intercurrent illness, contact with the PCP)

3. Document agreements or significant discussions regarding trial

administration, protocol violations, trial conduct, adverse event (AE) reporting, etc.

4. Save electronic media, originals, and/or certified copies

Considered an essential document per GCP

In the appropriate Regulatory Binder or participant’s research record at the site

ICH Guidance: E6 Good Clinical Practice:

8.3.11

Case Report Form

(See #25 of the Regulatory Binder)

Signed, dated, and completed Case Report Forms (CRFs):

Document that the investigator or authorized member of the investigators staff confirms the observations recorded

Document all changes/additions or corrections made to CRF after initial data were recorded

Sample data collection sheets and study questionnaires can be kept in the same section as the sample CRFs. Data collection sheets may act as source documents.

Considered an essential document per GCP

In the participant’s research record at the site

Keep the sample forms in the regulatory binder, along with any amendments; track as you would a protocol amendment

Check with the IRB about which sample CRFs and data collection sheets to submit

ICH Guidance: E6 GCP:

1.11

4.9.1-4.9.3

5.23.2

8.2.2

8.2.7

8.3.2

8.3.14

8.3.15

21 CFR 312

21 CFR 312.53; 21 CFR 312.62

Notes to File

(See #26 of the Regulatory Binder)

These may include site generated and/or sponsor generated notes to file. Sponsor generated NTF may be global or site specific.

A note to file should:

Be generated on a case-by-case basis
Include the subject and protocol it refers to
Be signed and dated by the individual who is writing it
Be legible if handwritten
Explain clearly and specifically the reason for the error/omission/discrepancy or process/policy it aims to address.
Should include any corrective action or follow-up when applicable.
Be filed with the document, subject file or behind the study binder tab to which it applies

If documents are maintained electronically, write a note-to-file indicating the

location and who maintains them (include copy of note-to-file here)

If documentation is filed separately, write a signed and dated note to file indicating the location (include note to file here).

In the participant’s research record at the site