MAY 2017 Vol. 17, No. 5; p. 49-60 INSIDE NIH Ethics Panel Vetoes Researcher: Human trials for Zika Human Infection Trials Zika could be safely performed...... 52 Cites risk to subjects, possible transmission IRB has many assessment tools to identify and fix problems...... 54 hile there are reports of trial approaches. various Zika vaccine trials Though a way forward is described Best Practices Spotlight: Wproceeding, one the most in the panel’s recent report to NIAID, Creating an optimal promising methods to quickly and for now a red flag has been raised and research training & accurately measure vaccine efficacy has human infection trials for Zika mentoring program. . . 56 come to a full stop. are being reconsidered. A researcher Conduct a QA/QI “Human challenge trials,” or who helped develop a controlled human research program risk “controlled human infection model for assessment...... 58 infection models,” dengue — which involve exposing “THERE ARE is closely related to research subjects to SPECIFIC Zika — questioned a pathogen, typically QUESTIONS the panel’s decision, in some attenuated saying it thwarts the state under rigorous WITH ZIKA THAT fastest method to controls and A CONTROLLED develop safe, effective oversight, to test a HUMAN RESEARCH vaccines. vaccine candidate. MODEL COULD “There are specific With regard questions with Zika to Zika virus, a REALLY ANSWER.” that a controlled committee human research convened by the model could really National Institute of Allergy and answer,” says Anna P. Durbin, MD, a Infectious Diseases (NIAID) has professor and researcher in the Johns concluded at present the risks of this Hopkins University Vaccine Initiative. approach outweigh the benefits. Among “I am not sure the committee had other reasons, the panel cited the risk to adequate information in making research subjects, possible transmission their recommendation. I think they to others, and the availability of safer overstepped. There is a pathway

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50 | IRB ADVISOR / May 2017 secondary transmission incidents zero. However, the mechanisms of be respected in challenge trials by that are concerning. These include transmission of Zika virus and how halting the collection of data for infection via needlestick to a lab long individuals with Zika can infect volunteers who want to withdraw worker, a case of female-to-male others are not fully understood. even if they will have to remain sexual transmission, and the strange Before proceeding with a Zika virus confined to protect themselves or case of a 73-year-old patient in the challenge study, researchers should others. U.S. who apparently transmitted Zika therefore demonstrate that the risks • In the event a Zika [human to a visiting acquaintance — possibly to third parties are not likely to be challenge] trial proceeds, study through tears — before dying with realized. sponsors should ensure that sites an incredibly high level of circulating • Whether a Zika virus human are adequately insured to cover the virus in the blood.2 The secondary challenge trial has sufficient social costs of care and compensation case developed symptomatic Zika value to proceed depends on the for research-related injury, to both infection, but subsequently recovered. reasons for conducting it and study participants and third parties, It is possible that hormonal treatment whether there are alternative ways and that insurance policies that are for prostate cancer somehow to obtain the information. The most purchased have adequate processes in accelerated viral replication in the compelling rationale for conducting place to efficiently and fairly evaluate index case, investigators concluded. a Zika human challenge trial, given and resolve claims. In addition, some people infected the risks and uncertainty, would • Community engagement with Zika have developed a rare be if field trials were prohibitively with the geographic community paralytic syndrome called Guillain- difficult to conduct in light of a surrounding the site(s) of a Zika Barré. waning epidemic. This rationale is human challenge trial should be not currently met, but could come to conducted in advance of the research pass in the future. Panel Recommendations to show respect for the community • A Zika virus human challenge and its values, obtain community trial only should enroll individuals buy-in to the goals of the research, In light of such concerns, the Zika with capacity to provide their and proceed with transparency. bioethics panel made the following voluntary . Such points and recommendations: a trial should also take steps to • There is substantial uncertainty minimize the risks to fetuses to as Committee Concerns about the risks to potential volunteers close to zero as possible. in a Zika virus human challenge • Researchers and sponsors of a IRB Advisor asked the following study. Although the known risks of Zika human challenge trial should questions of Seema K. Shah, a Zika human challenge trial appear use a robust informed consent JD, Zika committee chair and an comparable to the risks of Phase I process. For example, researchers associate professor at the Treuman research with healthy volunteers, and sponsors could require multiple Katz Center for Pediatric Bioethics without greater knowledge about voluntary steps for individuals at the University of Washington and outcomes from Zika exposure these to take to enroll, adequate time Seattle Children’s Research Institute. risks would require high social benefit for discussion, and evaluation of IRB Advisor: Just to clarify, given to be justified. and feedback given to enhance the current state of the science, does • The committee was particularly participant understanding about the committee recommend against concerned about possible risks to critical issues. conducting human trials that involve third parties, i.e., that Zika virus • Volunteers should be paid fairly intentionally infecting subjects with might be transmitted from study for their time and inconvenience, Zika virus? volunteers to others, such as fetuses but they should demonstrate Shah: The committee concluded and members of the community. understanding of the risks and that a Zika virus human challenge Because these third parties generally uncertainties involved and be study should not be conducted at cannot know about, protect evaluated with objective evidence this time, based on what we heard themselves from, or consent to of their eligibility and compliance about the state of the science, the risks, the risks are only reasonable wherever possible. risks to volunteers and community if they can be reduced to near- • The right to withdraw should members, the reasons for doing this

50 | IRB ADVISOR / May 2017 IRB ADVISOR / May 2017 | 51 type of research, and the alternatives. a number of safeguards were in place. to the possibility that a carefully The committee was concerned that We saw two compelling rationales designed Zika virus human challenge the full spectrum of disease caused for doing a Zika virus human trial could move forward. A Zika by Zika virus is not yet characterized. challenge study: One, if field trials virus human challenge trial might be However, the committee was become impossible to conduct, or ethically justifiable based on applying impressed by how much has been two, if human challenge trials could the latest scientific information to learned about Zika virus in the past accelerate development of a vaccine minimize risks, the small numbers of two years. that could prevent congenital Zika participants who would be enrolled IRB Advisor: Similarly, the infection. We did not hear evidence in a Zika virus human challenge trial, committee was particularly that the conditions we laid out are and the use of creative approaches concerned that Zika virus might be currently met, but we think they to minimize the risks to others so transmitted from study volunteers to could be met in the future. they are near-zero. In our report, we others, such as fetuses and members For example, although field provided a road map for researchers of the community. trials are being conducted now, the with concrete ethical issues to Shah: The committee was epidemic may burn out or become address and strategies for protecting concerned about the possibility of more unpredictable over time, volunteers and third parties. We did transmission to others outside of the making a human challenge study the not review any specific protocols and study, and recommended that a Zika only way to move vaccine research determine whether these conditions virus human challenge study should forward. Additionally, although we were met. Ultimately, the leadership not proceed until researchers can did not hear this evidence at our at NIAID will judge whether show that risks to others are unlikely consultation, regulatory agencies protocols they receive can meet to be realized. Research to learn more and other key stakeholders might the ethical conditions for moving about how Zika virus is transmitted clearly indicate that a Zika virus forward. n and how long individuals with Zika human challenge study would be virus are infectious is of high priority. an acceptable and important way to REFERENCES IRB Advisor: There are some speed up the licensure of a Zika virus 1 . Shah SK, Kimmelman J, Lyerly AD, safeguards mentioned in the report, vaccine. et al . Ethical Considerations for Zika such as “long-lasting reversible IRB Advisor: So there are Virus Human Challenge Trials: Report contraception.” Could research conditions that would meet the & Recommendations . February 2017: proceed if these type of safeguards are committee’s concerns and open a way http://bit .ly/2o6rjfm . in place? for this type of vaccine trial? 2 . Swaminathan S, Schlaberg R, Lewis Shah: The committee concluded Shah: With a compelling J, et al . Correspondence: Fatal that research could proceed if there reason to favor a Zika virus human Zika Virus Infection with Secondary was a strong enough rationale to challenge trial over alternative Nonsexual Transmission . New Engl justify the risks and uncertainty, and research designs, we were also open Jrl Med 2016;375(19):1907-1909 .

Researcher: Human Infection Trials for Zika Could Be Safely Performed

Imperative to begin testing vaccines while virus circulates

t sounds counterintuitive, but one in a large population. This very point was made during the I of the main arguments for getting Though there is less immediate massive Ebola epidemic outbreak a Zika virus vaccine into human trials need for a vaccine if the Zika virus in West Africa, where no vaccine is that as susceptible people become fades back, the problem is that no was available because it was not immune through prior infection, it vaccine will be available if it returns developed during past outbreaks of will be harder to test vaccine efficacy later to infect susceptible populations. the hemorrhagic virus.

52 | IRB ADVISOR / May 2017 One caveat that bears mentioning countries have fewer and fewer may be protective. With Zika, I think at this juncture: The CDC is urging susceptible people. So then you have we have a higher bar than we have vigilance and warning that Zika will to wait until there are new birth had with any other vaccine. Because return as the weather warms and cohorts that are susceptible. we know from the epidemiological Aedes egypti mosquitoes that carry the IRB Advisor: The Zika vaccine studies that have been done that in- virus emerge across a large swath of ethics panel report cited the risk of fection at any time during pregnancy the nation. transmission from study participants carries a risk. We know that asymp- An ethics panel recently advised to their contacts. What assurances to tomatic women have given birth to federal public health officials against you have that this would not occur? babies with microcephaly or Zika using controlled human infection Durbin: When you look at the congenital syndrome. You don’t have trials to test Zika vaccines, but said data, third-party transmission or to be symptomatic with Zika in order the model may be justified if the sexual transmission is not common. to transmit the virus to the fetus. So virus begins to wane. A researcher More than 40,000 travel-associated that makes us think that even small who developed a controlled human amounts of virus could be transmitted infection model for dengue virus to the fetus and result in congenital — which is closely related to Zika “THE REASON Zika syndrome. — questioned the panel’s decision WE THINK IRB Advisor: So that increases to red-light the approach, warning CONTROLLED the difficulty of developing a vaccine? that this may end up being a missed Durbin: As a vaccine developer, opportunity. HUMAN that tells us that we need a very high IRB Advisor asked Anna P. INFECTION bar of protection. We need to try to Durbin, MD, a professor and TRIALS ARE prevent any Zika virus from infection researcher in the Johns Hopkins VALUABLE IS YOU to the mother. When we look at University Vaccine Initiative, to most vaccines, we are looking to not discuss this point and explain how CAN HAVE A necessarily prevent infection because Zika vaccine controlled human VERY EARLY LOOK that is a very high bar, but you want infection trials could proceed safely. AT WHETHER to see aggregation of disease. People IRB Advisor: Are you concerned may become infected but they that Zika virus will diminish to the OR NOT YOUR don’t get sick. We don’t think that point that wouldn’t be able to test a VACCINE MAY BE is going to be enough with Zika. vaccine in a large population? PROTECTIVE.” You may have to actually prevent Durbin: I am absolutely infection, and you cannot study that concerned about that. If you look at in traditional efficacy studies because the data right now, this is the peak cases of Zika have resulted in some you won’t pick up asymptomatic season for Zika in South America, 40 cases of sexual transmission, which in Phase II or Phase III but they are seeing very few cases. is less than 1%. The big problem is trials. In Puerto Rico and the Caribbean that we don’t have very good data IRB Advisor: But you may be we may see some more cases this on shedding of actual virus that we able to overcome these issues with a summer, but I’m not convinced there can replicate. Everything is done by human infection protocol? will be enough Zika circulating by PCR, which doesn’t tell you whether Durbin: You can use a controlled the time a vaccine is ready to go into that virus is infectious — it only tells human infection model, where Phase III trials for efficacy studies. you that pieces of that virus were you vaccinate people [with a Zika It may become very sporadic like recovered. candidate vaccine] and then at some chikungunya virus or West Nile, IRB Advisor: What are the time point later — whether it is a and it will be difficult to predict advantages to using human infection month or six months, 12 months where it is circulating. You want to vaccine challenges? — you administer a known amount have a vaccine ready to go in case it Durbin: The reason we think [of virus] by subcutaneous injection. comes back. It needs a susceptible controlled human infection trials are We know exactly how much they population, and as it went through valuable is you can have a very early received. We administer it like we Brazil and South America, those look at whether or not your vaccine would any , drawing it up in a

52 | IRB ADVISOR / May 2017 IRB ADVISOR / May 2017 | 53 syringe and then injecting it under some kind of attenuated or weakened virus particles per ml. So we’re 100- the skin. Then we would follow Zika strain to induce the controlled to 1,000-fold below the level that [research subjects] very closely in human infection? would make people sick. inpatient settings for about two Durbin: When we think about IRB Advisor: So if you challenge weeks. We would sample blood and what would be a good Zika immune vaccine immunity with low titers probably urine, saliva, semen, and challenge, the first thing we want is of Zika, that would be unlikely vaginal secretions for women to an isolate from someone who had to transmit from the recipients to see if we can recover any virus. If uncomplicated Zika — so either a others? we recover virus, we would sample very mild illness or no discernable Durbin: That is exactly our using both PCR and old-fashioned illness. And then we would start intent. We don’t want transmission virology tissue culture to see if that with administering a very low dose. and we reduce the risk of that virus is replicating or not. If it is and So for the dengue model we found by giving a dose that low levels you recover virus, then you know that 100% of research subjects had of viremia in the recipients and that your vaccine did not induce replicating virus, but the virus is at a that’s what we have been able to sterilizing immunity. Then you low titer. It is 2.5 logs, about 300- do with the dengue controlled would have to decide whether it is 400 virus particles [per ml]. Whereas human infection model. It doesn’t worth using that vaccine. when people are sick with dengue replicate to high enough titers to be IRB Advisor: Would you use that have 10,000, 100,000, 1 million transmitted by mosquitoes. n

IRB Has Variety of Self-Assessment, Staff Assessment Tools

Responses help with continual improvement

n Indiana research compliance the assessment feedback confirmed After the IRB made changes Aprogram found that IRB staff there was a problem. and corrected what researchers and board assessments help keep the “That person is no longer a chair,” said was not working well, follow- program on track and running well. Baumann notes. up investigator surveys improved “The primary benefit of Assessments also can point out dramatically. assessments is to help us identify systemic problems. For instance, the “We made a lot of changes, and it problems we were not aware of and research compliance office responded went above 90% who said they were to confirm things we think we’re to an apparent IRB office crisis by satisfied or very satisfied,” he says. doing well to keep on doing them surveying researchers anonymously The organization originally began that way,” says John R. Baumann, about their experiences with the IRB. to create assessments as part of an PhD, associate vice president for “A few years ago, the office was in AAHRPP accreditation standard that research compliance at Indiana a real crisis; staff were demoralized, required that IRB members and staff University in Indianapolis. The researchers were unhappy with be periodically evaluated and given institution has seven IRBs with us,” Baumann recalls. “The IRB’s feedback. approximately 160 IRB members, turnaround and throughput were bad, This is accomplished via a variety including six chairs. so quantitatively and qualitatively, our of mechanisms, including member The following is an example of the measures were not very good.” self-assessment, assessment of IRB assessment’s use in identifying issues: The first survey had a good members by IRB staff, of IRB staff IRB staff and member assessments of response rate and made it clear that by IRB members, and researchers one IRB chair indicated a problem. the IRB had to make changes. “Our assessing the IRB process. “We had a feeling the person rate of satisfied or very satisfied was The staff’s survey of IRB members wasn’t performing that well as a 40% to 60%, depending on the was designed to provide insight into chair,” Baumann says, adding that question asked,” Baumann says. the working relationship between IRB

54 | IRB ADVISOR / May 2017 staff and individual board members, of staff requests, and responsive to period. Survey invitations go out to Baumann notes. communication. each principal investigator of a study “The first time we had the staff Based on the survey IRB members that is approved during those time evaluating IRB members was in complete about the staff, the IRB periods. 2013,” says Shawn Axe, CIP, director office has learned that its most “We ask a series of seven questions of the human research protection effective educational format is the 10- and we’re clear that we’re asking about program in the office of research 15 minute presentation by staff at the their experience with a particular compliance at Indiana University. start of board meetings, Axe says. approval,” Baumann says. “Then we Axe and Baumann explain how the “We have general regulatory have additional questions about the assessments work: or ethical topics and a PowerPoint time to approval, the new electronic • Staff assessment of IRB presentation, usually with an system, or things like that.” members and IRB members’ opportunity for questions and The researcher survey simply asks assessment of staff. “We evaluate answers,” Axe says. “This month, the investigators to answer each of six each IRB member based on how questions, based on ratings from often they worked with the member extremely unsatisfied to neutral on five or more areas,” Axe says. “We “THE PRIMARY to extremely satisfied. A seventh ask how well they understand the BENEFIT OF question is open-ended: “What can federal regulations and how well they ASSESSMENTS we do to improve these responses?” apply them.” Each question begins with “How The assessment also looks at how IS TO HELP satisfied are you with..: robust their documentation is and US IDENTIFY - Your working relationship with how accessible the member is. PROBLEMS WE the IU Human Subjects Office staff? The staff’s evaluation of IRB - The staffs’ pre-review/screening members is scored from one — WERE NOT of materials for review? extremely unsatisfied — to 5 — AWARE OF AND - Your IRB Chair? extremely satisfied. IRB employees TO CONFIRM - Your IRB Vice Chair? are advised to not score members THINGS WE - The qualifications and unless they are familiar with them. performance of the board? The following are the scoring THINK WE’RE - How the IRB meetings are run?” items: DOING WELL TO The narrow nature of the questions - ability to apply federal KEEP ON DOING has made the ratings more useful, regulations, ethical principles, and Baumann notes. IU IRB policies and procedures to THEM THAT WAY.” “It’s pretty much spot-on,” he research; says. “We don’t find very many petty - completion of reviewer topic was on promptly reportable comments or personal comments requirements: completed reviewer events, focused on unanticipated other than what is directly related to checklists, clear provisions (changes problems and noncompliance.” performance.” requested by the IRB reviewer to the Other topics have included The counterpart assessments IRB application), and presentation regulatory updates, vulnerable sometimes reveal an expectation or to IRB; populations, informed consent, communication problem. - accessibility: willingness to recruitment, and regulatory/ethical For example, one board member’s review minutes, willingness to compliance. assessment of IRB staff noted that consult with staff/investigators, The assessments are anonymous staff’s pre-review missed issues in willingness/timeliness of review and include room for comments. protocol submissions that the board expedited or high-priority “That’s how we found out the concern member felt should have been found submissions, and willingness to serve over one chair was pervasive,” Axe prior to the IRB meeting, Axe recalls. as an alternate or attend off-cycle notes. But the problem was not as it meetings; and • Researcher surveys about IRB appeared. The staff had done their - working relationship with staff: experience. Researcher surveys are jobs as they were instructed. They positive interactions, supportive held twice a year over a four-week conducted the pre-review for the

54 | IRB ADVISOR / May 2017 IRB ADVISOR / May 2017 | 55 purpose of identifying regulatory member to confirm the member is expedited reviews; and omissions in protocols. The issues the performing as expected, Baumann - Your participation in IRB board member raised were related to says. meetings.” grammatical errors. Self-assessments are identifiable, There also are several open-ended “Staff are not the grammar police and assessments also include a questions, including: and nor should they be,” Axe says. confidential set of questions that - What can we do to help you “These are not the things that hold up are not identifiable about the IRB improve as an IRB member? approval.” chair, vice chair, and staff. “We have - What additional educational So instead of changing how staff everyone reflecting and assessing resources may we provide? handled the pre-reviews, Axe spoke everybody,” Baumann says. - Any additional comments? with board members about how to The self-assessment form, like the The staff pull data about each IRB adjust their expectations of what the other assessments, asks for ratings member’s meeting attendance, CITI pre-review is intended to accomplish. from extremely satisfied to extremely completion, total new study reviews unsatisfied. for the full and expedited boards, and Perform Self- Members are asked to describe other information. “How satisfied are you with the Most assessments are positive, assessments following: and they’re given positive feedback - Your knowledge of the federal via email. “We might email to say, • IRB self-assessments. “We’ve regulations and ethical principles in ‘Everything looks good! Here’s your had self-assessment by IRB members research; appointment letter for the next and confirmation by chairs since - Your ability to apply the federal round,’” Baumann says. we’ve been accredited,” Baumann regulations and ethical principles in When IRB chairs and Axe meet says. “Every IRB member is required research; with IRB members or staff about to complete a self-assessment.” - Your knowledge of the IU IRB their assessments, it’s usually because The self-assessments include staff- policies and processes; there were red flags that have to be added performance data. - Your ability to apply the IU IRB addressed face-to-face. The IRB chair meets with policies and processes; “It’s always done with respect to Baumann or Axe and reviews the - Your attendance at IRB ,” Baumann says. “It’s board member’s self-assessment and meetings; all designed around, ‘How can we the IRB staff’s assessment of that - Your availability for conducting make you a better IRB member?’” n

Creating an Optimal Research Training and Mentoring Program

nine-year IRB chair veteran and Research Training and Mentoring in Baltimore. Edelman also is the A a medical school’s associate dean Program (CRTMP), a peer-to- director of the CRTMP at UMB and identified gaps in their institution’s peer, hands-on, protocol-specific an associate director for regulatory human research protection education. mentoring and training program. affairs and bioethics at the Center for They noticed that online training Often, investigators cannot relate Vaccine Development in Baltimore. was fine for general information, but what they learn online to their “You can go to a half-dozen came up short when investigators specific needs, saysRobert Edelman, classes and not solve the problem were struggling with specific protocol MD, clinical professor of medicine of a particular protocol,” Edelman issues. and pediatrics at the University says. “Each protocol is unique in its Their solution was the Clinical of Maryland School of Medicine own right, and there has never been

56 | IRB ADVISOR / May 2017 a protocol we have looked at that’s the school of medicine, though there investigators (PIs) who will benefit. exactly like another — there’s always also are requests from the schools The CRTMP works with principal some wrinkle to it that makes it of dentistry, social work, pharmacy, investigators, department/division different.” nursing, law, and regular graduate chairs, and the IRB and human school. “Sometimes faculty in the research protection staff to identify Time Savings, Increased school of law do healthcare research PIs and their protocols that would that requires questionnaires and benefit from the mentoring.1 Satisfaction interviewing people,” Edelman says. “You should have a feeling for the Here’s how the program works: needs of the investigator,” Edelman The CRTMP has proven 1. Advertise through suggests. “You have to empathize with successful. A study of its presentations. The program was their needs.” implementation showed that 179 described in presentations at 27 Many investigators are busy, of 2,340 protocols were assisted departmental meetings at six UMB distracted, and involved in research to by CRTMP. The program reduced professional schools. Other referrals the point that if they receive an IRB the number of protocols that were came from the IRB and UMB faculty deferral or modification, they feel returned for revisions by the IRB. networking.1 rejected, he notes. For non-assisted protocols, the “So I go in there and reassure mean number of returns were 1.6 “YOU CAN GO TO them that I really like the research, per protocol. For protocols assisted and it has to be done properly,” through CRTMP, the mean for A HALF-DOZEN Edelman says. returns was 0.7. For protocols that CLASSES AND He tells PIs that he’s giving them received the program’s assistance NOT SOLVE THE his time at no cost to the study while they still were in draft form, PROBLEM OF and that the mentoring program is the mean protocol returns was only supported by the president of the 0.4.1 A PARTICULAR university. This saved the IRB an estimated PROTOCOL. EACH 3. Customize one-on-one 1,291 hours of work, which equates PROTOCOL IS instruction. Edelman spends an to 161 person days saved over 4.5 average of six hours with each years, or 36 person days per year.1 UNIQUE IN ITS investigator in the mentoring Also, an anonymous CRTMP OWN RIGHT, program. The other mentor is a survey showed 100% satisfaction for AND THERE HAS professor of pediatrics, who also is 1 IRB chairs, vice chairs, and staff. NEVER BEEN A very experienced in human research About 95% of the protocols seen protection. in the program were successfully PROTOCOL WE “We read over the protocol and approved. The remaining 5% were HAVE LOOKED AT go into the science of it, if necessary, withdrawn by the investigator THAT’S EXACTLY and we review the regulatory after they were told their research requirements,” he says. was not going to be scientifically LIKE ANOTHER.” “We have a slideshow we bring valid or ethical because of a lack of with us and answer the questions volunteers, nursing staff, or other Edelman tells faculty and staff at their protocol demands from reading issues, Edelman says. presentations that the university feels off the slide principles,” Edelman “That’s an enormous time savings the protocol mentoring program is adds. “I tell investigators, ‘I am not for everybody,” he notes. “Those so important that they are willing to the IRB. I’m just a representative.’” few protocols can take an enormous invest his time and other staff’s time Edelman also explains that he amount of time of the IRB and panel to support it. cannot guarantee that everything he reviewers, going back and forth until “The knowledge that this is tells them will be approved by the they realize the study cannot be available to investigators does good IRB. done.” things to investigators at the highest “They understand that, but they Research requests for help through level,” Edelman says. also realize that we have an enormous the CRTMP come primarily from 2. Identify principal amount of experience,” he says.

56 | IRB ADVISOR / May 2017 IRB ADVISOR / May 2017 | 57 “I tell them I’ve spent years doing research blood bank. Edelman will call an administrator to IRB work and decades of work in Edelman meets with the help him solve the issue. clinical research — both international investigator and staff for an hour or 5. Stay with the PI until protocol and domestic,” Edelman says. “So two to focus on the protocol. He is approved or withdrawn. “When they respect my background.” answers their questions and reviews a PI gets the protocol approved, The goal is to work for the research their changes. it is a major sign that we’re on the participant’s welfare, addressing study “Sometimes I give them right track,” Edelman says. “I think volunteers’ rights, confidentiality, and suggestions on how to improve it, the program not only improves the ethical quality of the study, he but I always provide constructive the morale of investigators, but it notes. criticism, saying, ‘I’m now on your improves the morale of our HRPP “The investigators need to have team — I’m not the IRB. You can staff.” a certain mindset of caring for the take my advice or leave it as you From the staff’s perspective, the patient,” Edelman says. “Fortunately, wish,’” he says. mentoring program saves them time most of the time, they’re very much Although the CRTMP program and helps fill in gaps in their own in tune with their volunteers.” mentors researchers from a variety expertise. n 4. Help the PI strengthen the of scientific areas, Edelman is able to study’s design. The goal is to rescue help them answer scientific questions REFERENCE protocols that need help so they can after doing a little research. 1 . Edelman R, Campbell J, Doherty contribute to science and the world He says it’s his job to make J, et al . Clinical Research Training of medicine, Edelman says. them answer the hypothesis. “The and Mentoring Program (CRTMP) An example of a protocol’s issue regulatory requirements are the same, – A peer to peer approach – 2012- is one about kidney failure. The wherever they come from,” Edelman 2016 . Poster presented at PRIM&R’s study needed to answer questions notes. 2016 Advancing Ethical Research about obtaining informed consent, If an investigator has a question Conference, held Nov . 13-16, 2016, collecting blood, and use of a Edelman cannot answer, then in Anaheim, CA . Poster: 5 .

Conduct a QA/QI Research Program Risk Assessment

Assess the office that conducts assessments

uman research protection conduct formal risk assessments,” says thought it might be something H programs (HRPPs) are required Julie Moore, JD, MS, PA, associate other people could utilize in their to assess their quality, efficiency, director of research integrity and programs — whether they are IRBs and effectiveness if they’re seeking compliance at the University of South or QA/QI programs,” says Moore, accreditation. HRPPs can do this Florida in Tampa. who published a poster on the risk through ongoing quality assurance/ “Each of the programs did assessment project at PRIM&R’s quality improvement (QA/QI) a soup-to-nuts risk assessment, 2016 Advancing Ethical Research programs. But sometimes the quality writing formal reports describing Conference, held Nov. 13-16, 2016, improvement program also needs to the processes they went to and their in Anaheim, CA. be assessed for quality. determinations about their levels of Moore researched risk assessments This was what one research risk,” Moore says. for QA/QI and found very little institution decided. “Our assistant They also described processes that guidance. She and staff made a list vice president asked that every needed to be changed. of everything the office does and program in research integrity and “I found the risk assessment categorized items into bigger buckets compliance — all 13 of us — process to be very valuable and of activity.

58 | IRB ADVISOR / May 2017 “We take a look at each category “Our intention was to do a The risk assessment has been of activity that we do and look at detailed risk assessment of every turned into a narrative report related processes and procedures,” she program in research integrity and template. It starts with the executive explains. “Then we try to determine compliance,” Moore says. “But in summary, which is where the program where there might be risk that we the process of doing that, many staff can describe the program’s haven’t addressed well.” of our program managers realized activities in broad terms, Moore For example, in the QA/QI the formal process of conducting explains. program, activities can be divided a research process is applicable to There is space to list the risk into site audits and internal everyday activities done by each of assessment’s findings. Each is assigned monitoring, as they relate to the IRB our programs.” a risk and impact score, with activities and HRPP. There are full routine Each of the 13 divisions had rated from low to medium to high audits and informed consent-only six months to perform their risk risk. audits. IRB audits can be for cause assessments. The end result — the “There’s an executive summary in or routine. They also can be audits of risk assessment reports — were six to that graph, followed by a narrative site records and electronic IRB system 10 pages. of risk assessment,” Moore says. audits. “We have found them to be very “We break down each area and talk “We can go into our electronic helpful, for example, in justifying about the activities conducted in IRB system and make sure all the additional support that’s needed for that area and the standard operating approval letters contain the correct one of our programs,” Moore says. procedures we follow.” determination,” Moore says. “The risk assessment has served a They can provide justification “For-cause audits of studies dual purpose in that way: It’s not for the impact scores and are selected either by the board, only forced us to look critically at our recommendations for addressing chair, or IRB administrator, and processes, but it’s also highlighted any areas of risk, highlighted in each the process for conducting those is gaps.” area. straightforward,” Moore says. “We The risk assessment itself provides The most positive outcome of the looked at the most common findings necessary evidence to support asking risk assessment was the office’s ability for those audits and we tried to assess for more resources. “We can go up to to hire a full-time employee who is the sort of areas of risk on that end of senior leadership to say, ‘We did this dedicated to monitoring the IRB, it and how we could do a better job gap analysis and have this area where Moore says. of educating study teams.” there is a gap, and we need additional The goal now is to use the risk resources to close that loophole.’” assessment annually, she says. n Assessing the Assessors CME/CE OBJECTIVES

Other changes could include The CME/CE objectives for IRB Advisor are to help physicians and nurses be able to: revising HRPP policy to address areas 1 . establish clinical trial programs using accepted ethical principles for human subject of noncompliance. protection; “We also looked at all IRB record 2 . apply the mandated regulatory safeguards for patient recruitment, follow-up and reporting audits in previous years and identified of findings for human subject research; the most common findings,” Moore 3 . comply with the necessary educational requirements regarding informed consent and human subject research . says. It might be a little confusing to think of conducting a risk assessment of a program — like QA/ COMING IN FUTURE MONTHS QI — that, by its nature, conducts risk assessments. But Moore and „„Ethical challenges of precision „„Best practices in creating a central medicine IRB colleagues thought of the risk „„Strategies to increase IRB „„How to divide up local IRB review assessment of the QA/QI program education attendance and IRB of record review in terms of an overall look at the program’s activities.

58 | IRB ADVISOR / May 2017 IRB ADVISOR / May 2017 | 59 CME/CE INSTRUCTIONS

To earn credit for this activity, please follow these instructions: EDITORIAL ADVISORY BOARD 1. Read and study the activity, using the provided references for further research. Kay Ball, RN, PhD, CNOR, FAAN 2. Scan the QR code to the right or log on to AHCMedia.com, then select My Account to Associate Professor of Nursing take a post-test. Otterbein University Westerville, OH 3. Pass the online test with a score of 100%; you will be allowed to answer the questions as many times as needed to achieve a score of 100%. Paul W. Goebel Jr., CIP 4. After successfully completing the test, a credit letter will be emailed to you instantly. President 5. Twice yearly after the test, your browser will be directed to an activity evaluation form, Paul W. Goebel Consulting Inc. which must be completed to receive your credit letter. Monrovia, MD

Elizabeth E. Hill, PhD, RN Executive Director Research Service/Sierra Veterans’ CME/CE QUESTIONS Research & Education Foundation VA Sierra Nevada System Reno, NV 1. A Zika vaccine bioethics panel 3. Which of the following are gave which of the following scoring items for an IRB staff’s John Isidor, JD CEO, Human Subject Protection examples of measures that assessment of individual IRB Consulting, LLC may allow a controlled human members? Cincinnati infection trial to proceed? A . Ability to apply federal Lindsay McNair, MD, MPH, MSB Chief Medical Officer, WIRB-Copernicus A . Only enroll subjects that have regulations, ethical principles, and Group had previous Zika infection Indiana University IRB policies and Princeton, NJ B . Only enroll women using procedures to research Robert M. Nelson, MD, PhD effective contraception B . Principal investigator study Deputy Director C . Only enroll women who are experience, ability to listen Senior Pediatric Ethicist FDA permanently infertile carefully at IRB meetings without Washington, DC D . All of the above asking too many questions

James Riddle, MCSE, CIP, CPIA C . Age, culture, , Vice President of Client Services 2. The Zika panel stated that D . None of the above Kinetiq, a Division of Quorum Review IRB researchers and sponsors of a Seattle Zika virus human challenge trial 4. What are the benefits of a Susan Rose, PhD should use an informed consent mentoring program for principal Executive Director Office for the Protection of Human process that includes: investigators submitting Subjects protocols to the IRB? University of Southern California A . multiple voluntary steps for Los Angeles individuals to take to enroll A . Board members can get to B . adequate time for discussion know each investigator more Mark S. Schreiner, MD Associate Professor of Anesthesia and evaluation personally . and Critical Care C . feedback to enhance B . PIs can learn better University of Pennsylvania Executive Vice-Chair, participant understanding grammatical and editing Committee for the Protection of Human D . all of the above techniques for their protocols . Subjects C . Fewer protocols are returned The Children’s Hospital of Philadelphia to the IRB; staff save many hours Jeremy Sugarman of work . MD, MPH, MA Harvey M. Meyerhoff D . All of the above Professor of Bioethics and Medicine Johns Hopkins Berman Institute of Bioethics Department of Medicine Johns Hopkins University Baltimore

J. Mark Waxman, JD Partner, Foley & Lardner Boston