Risk-Benefit Ratio and Determinations. Sarah Mumford, Ammon Pate, Annie Risenmay IRB Operations Managers University of Utah

Risk-Benefit Ratio and Determinations Sarah Mumford, Ammon Pate, Annie Risenmay IRB Operations Managers University of Utah

Risk-Benefit Ratio and Determinations Nuances of Risk Determinations Direct Benefit Radiation Risks for Research Purposes Biopsy Risks for Research Purposes Exception From Informed Consent Nuances of Compliance/UP Determinations

Nuances of Risk Determinations Criteria for Approval Subpart D Children (Both DHHS and FDA) The IRB may approve studies involving children only if the research falls into one of the three following categories: 1. No greater than minimal risk 2. Greater than minimal risk but offers the prospect of direct benefit or may contribute to the well-being of the individual child 3. Minor increase over minimal risk and no prospect of direct benefit to individual children but likely to yield generalizable knowledge about child s disorder or condition

Nuances of Risk Determinations Considering Children in Research Placebos Breaking Out Segments of Research Two Categories Research Procedures Minor Increase Over Minimal Risk Two Parent vs One Parent Permission

Direct Benefit Additional Monitoring OHRP does not permit additional monitoring or more frequent follow-up to be considered direct benefit for research participation. The OHRP guidance reads: Relative to monitoring procedures: any benefit of monitoring listed in a 46.405 application must be an objective of the study and for approval under 46.405; the monitoring procedure must have the intended, not incidental, potential benefit of influencing the management of the individual child s disease. *46.405 refers to Children s Category 2 OHRP Discussion: Any benefit of monitoring must be a stated objective of the protocol. The monitoring procedure must have the intended, not incidental, potential benefit of influencing the management of the child s diseases or condition. Not acceptable to piggy back additional procedures of greater than minimal risk in a protocol under the guise of it being a monitoring procedure necessary for the child s care. Cannot justify non-clinically indicated biopsy that it might demonstrate some undetected problem Cannot justify MRI to study brain activity in children with ADHD by stating that the MRI could potentially provide benefit to the child by

Radiation Risks for Research Procedures Old Practice: Any radiation for research-only procedures is greater than minimal risk Does not account for type, amount, or location Working with Radiation Safety and Jeff Botkin to develop new more nuanced practice Additional guidance from Radiation Safety Committee for board consideration

Biopsy Risks for Research Purposes - Link to Board Member Guidance Guidelines apply to adults and children Extra consideration given for children Participant s underlying condition may impact determination (e.g. hemophilia, etc.) IRB can apply different guidelines a on case-by-case basis Skin Minimal Risk: Single <2mm, do not routine require sutures Minor Increase Over Minimal: Require sutures, usually includes punch biopsies Greater than Minimal: Any size biopsy on face due to motor nerves and arteries close to skin GI Tract, Transbrochial Lung, Brochial Wall May be Minimal Risk if during clinical endoscopy Addt l criteria (Number, Pt status, Frequency) Greater Than Minimal Risk If extra biopsy when others are taken for standard diagnostics Liver and Kidney Greater Than Minimal Risk

Slide 7 AR1 Email SlideGenius and ask for these graphics in red; right now they look very pixelated (difficult to manipulate color when they were white to begin with) Annie Risenmay, 1/26/2017

Exception From Informed Consent (EFIC)

What it is, and what it isn t Research "in a setting where the emergency circumstances require prompt action and generally provide insufficient time and opportunity to locate and obtain consent from each subject's legally authorized representative. (FDA 2013). It is not the same as emergency use of an investigational drug or device in a single patient. Emergency Use of a Test Article is when an investigational drug or device is used to treat a single patient outside a research study.

What should the IRB application materials include? 1. Justification for Study Design (EFIC Waiver) 2. Consent Process and ICF 3. Community Consultation and Public Disclosure Plan 4. Data & Safety Monitoring Board 5. IND and/or IDE from FDA

Justification for Study Design continued Obtaining consent is not feasible because: Patient medical condition prevents effective consent Intervention must be administered before LAR consent can be obtained No reasonable way to prospectively identify individuals who may be eligible Participation holds prospect of direct benefit because: Patients facing life threatening situation requiring intervention Appropriate animal/preclinical show evidence supporting the potential for direct benefit Appropriate risk/benefit ratio

Consent Process and ICF Must be performed as soon as is reasonable ICF must include all usual elements Researcher describes plan to attempt to obtain consent from LAR within therapeutic window (described in Protocol) when feasible If LAR consent is not feasible, researchers attempt to contact family members, and ask if they would object to participant s participation If participant condition improves, inform participant as soon as feasible If participant dies after enrollment (without LAR), LAR/family member(s) informed when feasible

Community Consultation & Public Disclosure Community Consultation Two way communication Goals are to show respect for individuals and community by listening to and acting on feedback

Public Disclosure Public Disclosure Plan for public disclosure to communities in which the investigation is conducted before study initiation. Plan for public disclosure after completion of the study to inform the community and researchers of study results, including demographic characteristics of participants

Data & Safety Monitoring Board Must be Independent, and must include all the usual elements of a Data & Safety Monitoring Board

Obtain an IND for IDE Planned Emergency Research Required even if the drug or device is already FDA approved for a specific indication

Board Review Key elements to focus on at board: Is the justification for the EFIC Waiver adequate? Is the Community Consultation and Public Disclosure plan specific enough?

IRB Approval Initial IRB approval is granted for a period of time (generally 6 months) to allow Community Consultation and Public Disclosure to take place. After which, PI submits Continuing Review with results of Consultation and Disclosure. At this point, the board can approve enrollment. At annual Continuing Reviews, the board should review PI s summary of efforts to contact LARs/family member(s) during the previous year.

Additional Guidance http://irb.utah.edu/guidelines/fda requirements/planned emergencyresearch.php

Planned Emergency Use Non-FDA Regulated studies

When does this situation arise? Study does not include investigational use of a drug or device, and is therefore not subject to FDA regulation Example: Emergency Department study randomizing to either: Cardiac Cath Lab or, Initial ICU admission

Justification for Study Design (EFIC Waiver) Patients in life threatening situation Available treatments unproven/unsatisfactory Collection of scientific evidence necessary to determine safety & efficacy Obtaining consent is not feasible Participation holds prospect of direct benefit because

IRB Requirements OHRP has not issued guidance for planned emergency research.

Board Review Key elements to focus on at board: Is the justification for the Waiver adequate? Is the Community Consultation and Public Disclosure plan specific enough?

Nuances of Compliance/UP Determinations

Report Forms Report forms are reviewed at the administrative level first o Not an unanticipated problem; o Not non compliance; or o Non compliance but not serious nor continuing non compliance. If the administrative reviewer or subcommittee reviewer believe the report is a possible UP or possible S/C NC, they forward it to the convened board to determine if the report represents: o An unanticipated problem o Non compliance, not serious or continuing o Serious and/or continuing non compliance

Deviations Serious Non Compliance An act or omission to act that resulted in significant harm (physical, psychological, safety, or privacy) or significantly increased the possibility of harm to the rights and welfare of research participants. Continuing Non Compliance A pattern of repeated actions or omissions to act that suggests a future likelihood of reoccurrence and that indicates a deficiency in the ability or willingness to comply with Federal regulations, VHA Handbooks or the policy, requirements, and determinations of the IRB governing human subject research.

Report Forms: Consideration Determinations may involve more than just black and white consideration.

Report Forms: Consideration Was the deviation reported promptly? Did the deviation harm any participants? Could it potentially have harmed participants? Were there any mitigating factors (e.g., something was not documented but was later found out to have taken place)?

Report Forms: Consideration Is the study still open? Status of the currently enrolled participants? Has the investigator had previous issues with non compliance, possibly in other studies/instances? (IRB staff has institutional knowledge.) What if the investigator does not agree with IRB determination?

Report Forms: Consideration How does the study team propose to correct the issue and prevent the deviation from occurring again? Corrective actions other than those proposed by the study team? Is suspension or termination of the study necessary?

Case 1: Description An investigator initiated study (with oversight by industry sponsors) is looking at a study drug treatment in participants with moderate, severe, and very severe aplastic anemia. Thirteen participants are enrolled at our local site, but the study is closed to enrollment with all study procedures completed. During a review of research records, it was noted there were several compliance issues, including: Various consenting and documentation errors including four participants who were seen and/or followed by physicians not listed on the 1572 and not having documented training on the protocol; Review of adverse events and assessment of blood smears were not consistently documented by the study investigators; Insufficient source documentation to determine proper drug accountability and participant adherence to dose escalation; Eligibility criteria had not been followed correctly; and Documentation of medical oversight and safety monitoring appeared to be lacking.

Case 1: Determination It was determined that the deviations described in the report constituted serious non compliance because: o Inclusion and exclusion criteria not followed; o SAE reporting guidelines not observed; and o Consent process (including documentation) not maintained. These deviations suggested the possibility of increased risk of harm to participants as a result of non protocol compliant enrollment procedures, inadequate drug accountability and documentation, and compromised data integrity.

Case 1: Corrective Actions The study was closed, so corrective actions were issued for future studies conducted by this investigator. o o o o o Follow SOP on Clinical Trial Participant Screening and Eligibility Review Assess toxicities for study drug discontinuation, dose modification, adverse events, and study stopping rules Document and verify accurate recording of data Required independent audit after the first two participants are enrolled Data cannot be used to submit to the FDA

Case 1: Follow-Up What if study had been open? If study personnel had not been listed in 1572 but had appropriate training? PI appealed to ask if he could still use data (publishing with better documented cases or noting data integrity issues in publication), board determined data was too compromised.

Case 2: Description Study testing memantine in stroke participants to see if it increases recovery during first three months post stroke. Nurse read instructions from EPIC stating participants should receive two 7mg tablets, but IDS issued bottles with 14mg tablets, and the nurse ended up giving two 14mg tablets to a participant. No adverse effects attributable to double dose; participant was not given medication the following day in order to titrate appropriate following this incident.

Case 2: Determination The board determined that this Report Form did represent non compliance but not serious or continuing non compliance. The issue lies in the level of the possibility of risk, since overdosing on any medication can produce detrimental effects. It is assumed the participants were informed of the risks on this study and that the risks of taking more of the medicine would fall within the already described risks of taking the drug, so it does not appear the rights of the participant were not compromised. Drug information from the protocol stated that the largest known ingestion of memantine worldwide was 2.0g, and the patient who took this dose experienced coma, diplopia, and agitation, but subsequently recovered; the participant here was given only 28 mg, much less than the highest overdose. Package insert states that the recommended target dose is 20 mg/day; no evidence that this amount of memantine increased risk to this participant.

Case 2: Corrective Actions o Update the EPIC instructions to more clearly reflect dosing instructions. o Create a plan/sop to reinforce that the nurse administering medication must double check the strength and the regimen prior to medication administration.

Case 2: Follow-Up What if participant had received more than the double dose? Would a similar type of deviation always be considered not serious non compliance?

Case 3: Description Study protocol requires that female participants receive a urine pregnancy test for screening and immediately prior to any vaccine inoculations, implying that the test must be negative. A female study participant received a urine pregnancy test prior to receiving a vaccine, but that vaccine was administered to her before the results of her pregnancy test had been processed. The study coordinator didn t realize that the pregnancy portion of the test results was absent until after inoculating the participant. The original urine test turned out to be compromised, so a second sample was collected, and proved to be negative.

Case 3: Determination It was determined that this event represents serious non compliance; while the board recognizes that no actual harm occurred in this specific event, there was the potential for significant harm if the pregnancy test had in fact been positive.

Case 3: Corrective Actions Study coordinator counseled and retrained on the importance of following protocol requirements with an emphasis on pregnancy testing, patient safety, and GCP. Study team instructed not to administer future inoculations until a negative pregnancy test result can be verified.

Case 3: Follow-Up Would we have handled this differently if participant had been pregnant? Could there have been any mitigating factors that would have changed the serious non compliance determination?