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Winter 2021 RESEARCH MATTERSKARMANOS RESEARCHERSPUBLISH ARTICLE IN ‘NATUREREVIEWS CLINICAL ONCOLOGY’Karmanos Cancer Institute is pleased to announce that the work of RamziMohammad, PhD, member, Molecular Therapeutics Research Program, KarmanosCancer Institute andWayne State UniversityCLINICALSchool of Medicine (WSUONCOLOGYSOM), and Asfar Azmi,PhD, co-leader, TumorBiology and Microenvironment Research Program, Karmanos Cancer Institute andassistant professor, WSU SOM, has been published in a comprehensive reviewarticle in “Nature Reviews Clinical Oncology.”natureREVIEWSThis publication, which is co-authored by Hafiz Uddin, PhD, postdoctoralfellow, Department of Oncology, WSU SOM, continues their successful basic,translational and clinical research on nuclear protein transport pathways. Thecomprehensive article covers the biology of protein transport and the pre-clinicaland clinical development of small molecule inhibitors that target this importantprotein. The article is published at: (https://pubmed.ncbi.nlm.nih.gov/33173198/)This group has spent more than a decade researching the pre-clinical developmentof nuclear transport inhibitors. Their work was critical in developing Selinexor(XPOVIO), a drug that is now Food and Drug Administration (FDA)-approved forthe treatment of cancer patients with relapsed or refractory multiple myeloma andnon-Hodgkin’s lymphoma. The drug was also introduced in a global COVID-19clinical trial. Karmanos served as one site for the study. Selinexor is now beingdeveloped further under the Cooperative Research and Development Agreement(CRADA) with the National Cancer Institute’s (NCI) Cancer Therapy EvaluationProgram (CTEP). Several national clinical studies are planned.“Protein movement within cells is important for their normal function,” explainedDr. Mohammad. “Such movement is guided by specialized carrier proteins ortransporters. Exportin 1 or XPO1 is the major exporter of nuclear proteins. Incancer, XPO1 becomes hyperactive and displaces the tumor suppressors to theincorrect compartment, thereby inactivating their function. XPOVIO is a drug thatblocks such transport and retains the tumor suppressors in the correct cellularcompartment and allowing them to control tumor growth.”“This is a joint effort beginning from our basic science group, which was supportedby collaborative pharma partner Karyopharm Therapeutics Inc., as well as clinicalinvestigators at Karmanos who collectively helped move a concept from the labto FDA approval. We continue to find ways to improve the efficacy of this drugthrough the discovery of novel combinations. There is a need to identify prognosticand therapeutic biomarkers that could guide a more tailored XPOVIO therapy andis currently being intensively investigated by our group,” Dr. Azmi said.In line with this project, the team is currently conducting correlative researchon two active clinical studies at Karmanos. The first is a National Institutes ofHealth (NIH) Method to Extend Research in Time (MERIT) Award-funded studyon pancreatic cancer. This study is being led by Philip Philip, MD, PhD, FRCP,leader, Gastrointestinal and Neuroendocrine Tumor Multidisciplinary Team (MDT)at Karmanos Cancer Institute, professor, WSU SOM. The second study is on nonHodgkin’s lymphoma and is led by Erlene Seymour, MD, member of the MalignantHematology MDT, Karmanos Cancer Institute, assistant professor, WSU SOM,CONTINUED ON PAGE 165

Winter 2021 RESEARCH MATTERSRESEARCHAROUNDMcLARENKARMANOS CANCER INSTITUTELAUNCHES CLINICAL TRIALS STUDYINFORMATION PORTALKarmanos Cancer Institute is pleased to announce the launch of a new clinicaltrials study information portal (SIP) on Karmanos.org. This portal was launched onMonday, November 9, 2020.The SIP website, which is integrated with OnCore Clinical Trials ManagementSystem, is used by medical professionals, researchers and the general public tosearch clinical trials recruiting at Karmanos. The site allows users to easily search,sort and navigate through the many clinical trials available at Karmanos CancerInstitute.Features include:n Principal investigator profilesn Eligibility criteria from clinicaltrials.govn List of studies on related-physician profilesn Location maps and phone numbers of study sitesn Search fields including cancer multidisciplinary team/type, investigational device,NCT ID and multiple search termsn Mobile-friendly design (Note: The Karmanos Clinical Trials Mobile App will stillbe available).Additional features are expected to go live in the coming months. To view the newportal, visit www.karmanos.org/opentrials.“The launch of the clinical trials study information portal allows us to better serveour patients and creates greater ease for our physician partners and researchersas they explore Karmanos’ clinical trial offerings. We are proud to offer more than800 clinical trials to give patients access to tomorrow’s care today. By creatingan easier way to organize information about these trials, we can ensure that thesetreatments reach all patients who are eligible,” said Gerold Bepler, MD, PhD,president and CEO of Karmanos Cancer Institute.The Barbara Ann Karmanos Cancer Institute has one of the largest and bestclinical trial programs in the United States, giving patients better access to newcancer treatments. Our patients have access to more than 250 promising newcancer treatments often available only at Karmanos Cancer Institute. Karmanos haspatients actively participating in more than 800 clinical trials, which are developedand sponsored by our own physicians and researchers, major pharmaceuticalcompanies or national cooperative group programs funded by the National CancerInstitute (NCI).This allows us to offer patients treatments that are often not available anywhereelse. In fact, one-third of all new cancer drugs were developed with ourparticipation in trials. As the state’s only hospital focused solely on cancer,we take our research role seriously while also delivering care with the utmostcompassion and understanding. With our long-term partnership with the WayneState University School of Medicine, we are committed to promoting excellencein cancer research, education and clinical care. To speed treatments from thelaboratory to the patient’s bedside, our partnership represents a synergisticcollaboration between the laboratory scientists, cancer experts and clinicians whointeract directly with patients. Together, we have conducted research that hascontributed substantially to therapeutic breakthroughs in cancer and that continuesto define new standards of care.6

Winter 2021 RESEARCH MATTERSKARMANOS CANCER INSTITUTERECEIVES RENEWAL OF NATIONALCANCER INSTITUTE (NCI) CORE GRANTThis renewal extends Karmanos’ 42-year history of prestigious designationas one of only 51 Comprehensive Cancer Centers in the nationThe Barbara Ann Karmanos Cancer Institute is pleasedto announce that its National Cancer Institute (NCI) CoreGrant has been renewed. This renewal extends Karmanos’prestigious NCI designation through 2025. Karmanos isamong 51 centers nationwide to receive this designation.NCI-designated cancer centers are characterized byscientific excellence and the capability to integrate a diversityof research approaches to focus on the problem of cancer. They play a vital role inadvancing towards the goal of reducing morbidity and mortality from cancer.“This designation reaffirms what we see at Karmanos every day: that ourresearchers and clinical staff members are doing outstanding work in their fields,”said Gerold Bepler, MD, PhD, president and CEO of the Barbara Ann KarmanosCancer Institute. “Our NCI designation sets us apart in the fields of cancerresearch and treatment by showing our patients, colleagues and peers that weare committed to creating a world free of cancer. With this achievement, we areempowered to press forward in the fight against cancer.”To secure grant renewal, Karmanos submitted a 2,000-page application andunderwent a site visit by a panel of experts from across the country. The 2020 visittook place virtually for the first time in history, due to the COVID-19 pandemic. Thisvisit resulted in a detailed report including a score sheet. We are proud to reportthe work of Karmanos’ Office of Cancer Health Equity and Community Engagement(OCHECE), which conducts community-based behavioral research, achieved aperfect score of “exceptional”. Overall, Karmanos exceeded its standing from 2015 –a result that validates the hard work and dedication of the Karmanos team.The NCI first designated the Barbara Ann Karmanos Cancer Institute as acomprehensive cancer center in 1978, when the Institute was called the MeyerL. Prentis Comprehensive Cancer Center of Metropolitan Detroit. It was the firstcenter in Michigan to receive the NCI designation and remains one of only two inMichigan with this title.To be designated as a comprehensive cancer center by the NCI, a center must:n Demonstrate a depth and breadth of cancer research activities in each of threemajor areas: basic laboratory, clinical and prevention control in population-basedsciencen Be effective in serving their catchment area, as well as the broader population,through the cancer research they support and the cancer control activities theyundertaken Integrate cancer training and education of biomedical researchers andcommunity health care professionals into programmatic efforts to enhance thescientific mission of the centern Initiate and conduct early-phase, innovative clinical trials and participate in theNCI’s cooperative groups by providing leadership and recruiting patients for trialsn“The renewal of the Core Grantby the National Cancer Institutereinforces Karmanos CancerInstitute’s status as one of the bestcancer treatment and researchoperations in the mid-west and thelargest in the state of Michigan.This renewal is the result of thehard work and dedication of ourclinicians and researchers andenables us to provide bench-tobedside medicine to our patients.We are grateful for the renewal ofthis NCI designation, as it allowsus to provide critical resourcesand develop life-saving cancertreatments in the communities weserve. We can only imagine thecontinued advances in treatmentprotocols that will come from thisachievement. No doubt, many liveswill be saved.”– Philip A. IncarnatiPresident and CEOMcLaren Health CareConduct activities in outreach and education and provide information onadvances in health care for health care professionals and the publicKarmanos has met these criteria and is pleased to share highlights from our list ofaccomplishments. In the past five years:CONTINUED ON PAGE 197

Winter 2021 RESEARCH MATTERSRESEARCHAROUNDMcLARENKARMANOS CANCER INSTITUTEAND WAYNE STATE UNIVERSITYAPPROVED FOR A 149,324ENGAGEMENT AWARD FOR PROJECTON COVID-19A team at Karmanos Cancer Institute and Wayne State University has beenapproved for a 149,324 funding award through the Eugene WashingtonPatient-Centered Outcomes Research Institute (PCORI)Engagement Awards program to support a new project:“Supporting Detroit Communities as Leaders and Partnersin COVID-19 Research.” The funds will support a COVID19-related project enhancement to the previously fundedand ongoing project, “Best Practices to Engage Black Menin the Development of a Cancer Health Equity Research Agenda.”The project is co-lead by Jinping Xu, MD, professor in the Department of FamilyMedicine and Public Health Sciences at Wayne State University, and HayleyThompson, PhD, associate center director, Community Outreach & Engagementand faculty director of the Office of Cancer Health Equity and CommunityEngagement, Karmanos Cancer Institute, and professor in Department ofOncology, Wayne State University School of Medicine.The project will focus on developing a community-informed COVID-19 researchagenda and is currently recruiting members for two COVID-19 Action Councils.These groups will work to reduce COVID-19-related health disparities byengaging community members as partners in local COVID-19 research.Additionally, council members will have the opportunity to serve on a communityresearch review board at Wayne State as part of a system to integrate communityinterests into research and ensure transparency. COVID-19 survivors, caregivers,essential workers, first responders and advocates from the metropolitan Detroitarea are invited to apply. For additional information about the COVID-19 ActionCouncils and to access the application, visit ncil.“We are thrilled to have this additional funding from PCORI to develop theCOVID-19 Action Council so we may better understand the impact COVID-19 onour local communities and the necessary steps to reduce health disparities thathave been exposed by COVID-19,” said Dr. Xu.8

Winter 2021 RESEARCH MATTERS“Traditionally, everyday people have been excluded from academic medicalresearch, and community priorities and values are not typically considered.We’re excited to work with our community partners – Detroit Parent Network, theFaith-Based Genetic Research Institute, LGBT Detroit and Community-CampusPartnerships for Health – to amplify community voices and perspectives on theCOVID-19 research taking place in our city and region,” Dr. Thompson said.This COVID-19 project, as well as the original project, are part of a portfolio of projectsthat PCORI has funded to equip patients and other stakeholders to participateas partners in comparative clinical effectiveness research (CER) and disseminatePCORI-funded study results. Through the Engagement Award Program, PCORI iscreating an expansive network of individuals, communities and organizations interestedin and able to participate in, share and use patient-centered CER.According to PCORI’s Chief Engagement and Dissemination Officer JeanSlutsky, “This project was selected for Engagement Award funding because itwill help the community increase their capacity to participate across all phasesof the PCORI/CER process while responding to contextual changes as a resultof the COVID-19 pandemic. We look forward to working with Wayne StateUniversity and Karmanos throughout their 2021 project.”Wayne State University’s project and the other projects approved for fundingby the PCORI Engagement Award Program were selected through a highlycompetitive review process in which applications were assessed for their abilityto meet PCORI’s engagement goals and objectives, as well as program criteria.For more information about PCORI’s funding to support engagement efforts, agement-awards.PCORI is an independent, nonprofit organization authorized by Congress in2010 to fund comparative effectiveness research that will provide patients,caregivers and clinicians with the evidence needed to make better-informedhealth and health care decisions. PCORI is committed to seeking input from abroad range of stakeholders to guide its work.COVID-19 PANDEMIC BRINGSNEW INVESTIGATORS TO MCRICONTINUED FROM PAGE 3“We reached out to Infectious Disease Specialists, Critical Care Specialists, andPulmonologists for our COVID related Phase II drug studies, and have engageda number of physicians who are now participating in clinical trials for the first timewith MCRI,” explained Pam Wills-Mertz, “It’s exciting to work with new therapeuticareas, new physicians and spread awareness of the McLaren Center for Researchand Innovation.”Becoming an investigator on a clinical trial is a process that involves additionaltraining, certification, and extra time to devote to your coordinator, study patientsand the study sponsor. Sponsors have rapid timelines and expect a high degreeof attention and turn around on data entry and queries. With the help of MCRIand your local coordinator, together we can make this an exciting and rewardingaddition to your medical career.Please contact McLaren Center for Research and Innovation if you have questionsor are interested in conducting a clinical trial at McLaren. MCRI@mclaren.org(248) 484-4950.9

Winter 2021 RESEARCH MATTERSEQuIPCORNERPROTOCOL DEVIATIONS VS.PROTOCOL VIOLATIONS:DEFINITIONS, REPORTINGGUIDELINES, AND PREVENTIONBy Andrea Klaver, MBA, CHRCConfusion often exists surrounding the similarities or differences of a protocoldeviation and a protocol violation. In fact, it continues to be one of my most-askedquestions from different research communities throughout my time as a researchcompliance professional. In this edition of EQuIP Corner, we will review thedifferences between a violation and a deviation, identify ICH/GCP, Federal, andIRB reporting requirements for violations and deviations, and discuss actions thatmay help to prevent them from occurring in the first place.It is important to note that the terms protocol deviation and protocol violation havedifferent meanings and should not be used interchangeably. Although, a pattern ofrepeated protocol deviations of the same nature may constitute a protocol violation.Protocol DeviationsA protocol deviation occurs when study activities diverge from the IRB-approvedprotocol without prior sponsor and/or IRB approval. Deviations may be considereda simple variance from the protocol, whether accidental or unintentional. Deviationsdo not increase risk or decrease benefit to the study subjects.That is, deviations do not have a significant effect on (1) study subject’s rights,safety, or welfare; and/or (2) the integrity of the study data. Examples of a deviationmay include:nA rescheduled study visitnFailure to collect a supplementary self-report questionnairenVital signs obtained prior to informed consentProtocol ViolationsA protocol violation occurs when there is divergence from the IRB-approvedprotocol (a deviation) that also (1) impacts a study subject’s rights, safety, orwelfare, (2) reduces the quality or completeness of the study data; or (3) affectsthe scientific integrity of the study. Violations generally increase risk or decreasebenefit.10

Winter 2021 RESEARCH MATTERSViolations may still be considered accidental or unintentional change to, or noncompliance with, the IRB-approved protocol. Examples of protocol violations mayinclude:nInadequate informed consent (obtained informed consent on a non-datestamped form)nMultiple visits missed or outside permissible windowsnAccidental use of prohibited medication or dosenEnrollment of subjects not meeting the inclusion/exclusion criteriaWho is Responsible for Deviations and Violations?Deviations and violations may result from the action of the study subject, studyteam, or other research staff. These individuals, along with auditors, monitors,regulatory staff, or other hospital staff are responsible for helping to assureprotocol compliance and identify non-compliance.Through the collaboration of these groups, a strong safety net is created tominimize the occurrence of deviations and violations. Is the informed consentre-affirmed before each visit, each procedure, and for each participant? Can weconfirm the informed consent form is for the correct study, both before and afterthe consent process? Do the labs being drawn match what is in the IRB-approvedprotocol? These are just a few examples of instances within the study where wehave the opportunity to strengthen the safety net.Reporting GuidelinesICH/GCP guidelines (Section 4.5 “Compliance with Protocol”) state that “theinvestigator/institution should conduct the trial in compliance with the protocolagreed to by the sponsor and approved by an IRB.” Furthermore, the guidelinesask that investigators do not “implement any deviation from, or changes to, theprotocol without agreement by the sponsor and approval from an IRB, exceptwhere necessary to eliminate an immediate hazard(s) to trial subjects.”In this guidance, the word “deviation” is used to convey the notions of bothdeviations and violations. Although, as discussed above, the terms should notbe used interchangeably. Deviations by definition do not have a significant effecton a study subject’s rights, safety, or welfare, so they will not inherently be usedto eliminate immediate hazards or be reported as such. These situations aredescribed and reported as violations.The FDA does not distinguish between a deviation and a violation; all protocolvariances are deviations. Here, the term deviation is not defined by either HHS(OHRP) human subjects regulations (45 CFR 46) or FDA human subjectsregulations (21 CFR 50).At McLaren, protocol violations must be reported to the IRB within 10 workingdays of the study team’s knowledge of the occurrence. Protocol exceptions (a onetime enrollment of an individual who does not meet current IRB-approved criteriafor inclusion in the research study as outlined in the protocol) require prior approvalfrom the IRB and the study sponsor, if applicable, prior to the enrollment of thesubject. Protocol deviations (an occurrence that does not meet the definition ofexception or violation) are to be recorded by the investigator and submitted to theIRB at the time of the

accelerated timeline, with an already heavy workload. MCRI graciously thanks the team at McLaren Oakland for the extra time and effort put forth to support this new clinical trials office and the first open and enrolling trial at this institution. We look forward to providing more research opportunities for the McLaren Oakland patient population in