Dartmouth Human Research Protection Program (HRPP) Data Safety Monitoring and Reporting requirements Brown Bag Series: Noon / First Tuesday of the Month April 4th, 2017 - Auditorium B

Updates New initiatives: AAHRPP update New initiatives: Improving the consent process; VoICE; new regulations Education for new research staff May: Leigh Burgess – clinical trial.gov; Scientific Review Process update

Questions during this session?  Email Ann O’Hara and we will try to respond during our Q&A following the presentation: ann.ohara@dartmouth.edu Liz.bankert@dartmouth.edu

Reporting : Sponsor FDA Local IRB External IRB OHRP PI / multi site study FDA Local IRB PI = sponsor Investigator initiated IND holder Institutional Officials External IRB OHRP

Monitoring Guidance : NIH FDA GCP – Good Clinical Practice

NIH: "a variety of types of monitoring may be anticipated depending on the nature, size, and complexity of the clinical trial. In many cases, the principal investigator would be expected to perform the monitoring function."

NIH: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III); etc. Monitoring should be commensurate with risks Recommend conclusion of the trial when significant benefits or risks have developed or the trial is unlikely to be concluded successfully. Risk associated with participation in research must be minimized to the extent practical. Commensurate with size and complexity.

Food and Drug Administration Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring

The regulations are not specific about how sponsors are to conduct such monitoring and are therefore compatible with a range of approaches to monitoring (see section III) that will vary depending on multiple factors (see section IV.C).

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE GUIDELINE FOR GOOD CLINICAL PRACTICE (GCP) E6(R1)

4.11 Safety Reporting 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.

4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports)

Reporting to the IRB is a subset of other reporting requirements

46.111 Criteria for IRB approval of research First: Before any reporting starts – the IRB is responsible to ensure monitoring is in place : 46.111 Criteria for IRB approval of research (6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

45CFR46.103 Reporting - IRB (5) (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval.

Reporting to IRB includes: Retrospective protocol deviation: RNI Prospective protocol deviation : modification Continuing Review

Reportable New Information (RNI) CPHS Reporting Form : Unanticipated Problems Involving Risks to Subjects or Others (UPRs), Serious Adverse Events (SAEs), and Unanticipated Adverse Device Effects (UADEs)

Reporting criteria differs based on whether the occurrence was internal or external. An internal event is one that involves a Dartmouth site or another CPHS-reviewed site or a Dartmouth research participant (regardless of location of the participant at the time of event). External events are those that occur at a non-CPHS reviewed site and with participants that are not research participants under CPHS oversight. This also refers to important new information that goes beyond discrete, individual events, such as: IND Safety Report, new animal data, or a black box warning.

Timeframe for reporting: Applies to medical and non-medical problems, and includes potential risks that did not lead to direct harm. 5 calendar days for the temporary or permanent suspension of current activities to avoid potential harm of participants or others. 10 calendar days for both Internal and External Events that meet reporting criteria, but did not lead to suspension.

The investigator is reporting this incident to: ☐ CPHS only ☐ Sponsor ☐ Other (e.g., program officer): __________________________ 4. Has this event been reported to the FDA, OHRP, and/or others? ☐Yes ☐No* *If no, does the sponsor intend to do so? ☐Yes ☐No 5. Study location: ☐ Multi-site ☐ Dartmouth Only (sites subject to CPHS review)

Is the risk of this event described in the consent form or in the investigator's brochure? ☐ No ☐ Yes, but it has occurred with greater specificity ☐ Yes, but it has occurred with greater frequency ☐ Yes, but it has occurred with greater severity ☐ Yes, but none of the above (this does not meet CPHS reportability criteria,do not report unless study modifications are planned which are directly related to this event/risk). Explain here:

Describe the response as a result of this event/problem: Describe the plan to protect or notify currently enrolled individuals regarding this event: Is a modification to the study expected from the sponsor?

Thank you for your time. Questions during this session?  Email Ann O’Hara ann.ohara@dartmouth.edu CPHS.tasks@dartmouth.edu