Protocol Review Committee Research Articles

Challenges in assessing the efficacy of systemic corticosteroids for severe wheezing episodes in preschool children

Summary This letter addresses the controversial issue of the use of oral corticosteroids during wheezing exacerbations in preschool-aged children by demonstrating findings of a prematurely terminated multi-center clinical trial, discussing lessons learned, and suggesting future directions.

Abstract 4764: An analysis of factors associated with oncology clinical trial activation at University of Illinois Cancer Center Oncology Clinical Trials Office

Abstract Background & Objective The time from conception to the initiation of clinical trials has been described as costly and time-consuming because of administrative processes (Martinez, D. A. et al). The long clinical trial activation period results in delay in data and affects evidenced-based medical practice. Long clinical trial activation times may be associated with a variety of factors. The objective of this research is to identify and assess factors that impact clinical trials activation periods at the University of Illinois Cancer Center Oncology Clinical Trials Office (UICC OCTO). Methods A protocol search for UICC OCTO managed studies was generated in OnCore. The search was limited to trials that were activated from January 1st, 2016 through November 30, 2017. Time to activation was defined as the time of protocol submission to the Protocol Review Committee (PRC) to the time the study was opened to accrual. Studies which were PRC approved in 2016 but attained Open to Accrual status in 2017 was counted as part of 2016 studies. Time to activation differences between 2016 and 2017 studies was assessed by IIT, Sponsor Type, Institutional Review Board (IRB) Review Type and Study Type. Results A sample of 22 studies (Calendar Year 2016, 12; Calendar Year 2017, 10) was identified. The average activation time was 206.8 days for calendar year 2016 and 78.2 days for calendar year 2017. Results indicate that the activation time generally decreased in 2017 regardless of Sponsor Type, IRB Review Type or Study Type but not whether the study was interventional or not. The average time to activation for interventional studies decreased in 2017 but remained similar for non-interventional studies. Notably, average activation time was longer for non -IIT and Industry studies for both years. Conclusions Clinical trial activation times at the UICC OCTO decreased from 2016 to 2017. The mix of study Sponsor Type, IRB Review Type or Study Type between the two years was similar, and the decrease between the years appears to be independent of these variables. Therefore, it can be inferred that the decrease in activation time was due to interventions made to the process between the two years. These interventions included increase in staff, reorganization in staff duties including moving all activation oversight activities to a new start-up coordinator position, and process changes implemented to increase efficiency. These results should take into consideration that 50 % of studies submitted to the PRC in 2017 will roll over into 2018 for activation, and are therefore not included in the 2017 sample. The data will be reanalyzed at a later time to capture the activation time for all studies started in 2017. In addition, activation time will continue to be tracked to see the effects of additional process changes. Citation Format: Mary A. Otoo, Michelle Uriostigue Preza, Margaret Gavor, Darlene Kitterman, Oana Danciu. An analysis of factors associated with oncology clinical trial activation at University of Illinois Cancer Center Oncology Clinical Trials Office [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4764.

The Impact of Chemotherapy on Survival of Patients with Extremity and Trunk Wall Soft Tissue Sarcoma: Revisiting the Results of the EORTC-STBSG 62931 Randomised Trial Using Sarculator, a Validated Nomogram-Based Risk Assessment Tool

BACKGROUND: To determine whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT) which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs). METHODS: A retrospective analysis of the EORTC-STBSG 62931 RCT was performed on individual patient data of study participants with extremity and trunk wall STS (N=290/351). 10-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped in three categories of predicted pr-OS: high (pr-OS > 66%), intermediate (51< pr-OS ≤ 66), and low (pr-OS ≤ 51%). OS and disease-free survival (DFS) were calculated at the study median follow-up (8-year). FINDINGS: Nomogram pr-OS were dispersed (median 72%, IQR 57-83%) and had prognostic value for OS and DFS (Log-Rank test: P<0·001). 170 patients had high pr-OS (58·6%, 90 Obs/80 Adj), 68 intermediate (23·5%, 34 Obs/34 Adj) and 52 low (17·9%, 24 Obs/28 Adj). Adjuvant chemotherapy halved the risk of recurrence (HR=0·46, 95%CI 0·24-0·89) and death (HR=0·46, 95%CI 0·23-0·94) in the low pr-OS category, while no effect was detected in the intermediate and high pr-OS categories. In order to strengthen these findings, study participants with predicted pr-OS<60% were combined (N=80, 27·6%, 39 Obs/41 Adj) and a significant benefit in terms of DFS (HR=0·49, 95%CI 0·28-0·85) and OS (HR=0·50, 95%CI 0·30-0·90) was detected. INTERPRETATION: Patients of the EORTC-STBSG 62931 RCT with extremity and trunk wall STS and a low predicted pr-OS (i.e., high-risk patients) had a better outcome when treated with adjuvant chemotherapy. This may help reconcile the somewhat disparate results of published clinical studies on adjuvant/neoadjuvant chemotherapy in high/risk STS. Funding Statement: This was an academic non-funded study. The EORTC-STBSG 62931 trial was funded by European Organisation for Research and Treatment of Cancer (EORTC) and Rhone-Poulenc-Rorer. Declaration of Interests: The authors declare they have no conflicts of interest. Ethics Approval Statement: The protocol of the EORTC-STBSG 62931study was approved by the EORTC Protocol Review Committee and institutional review boards. The patients gave informed consent according to applicable laws in all participating countries. The current study was approved by EORTC through the ‘Request for data platform’.

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

SC15.04 The Japanese Perspective

In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started. JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986. Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014. Japan Clinical Oncology Group, West Japan Oncology Group, Investigator initiated multicenter clinical study

Prospective Implementation of Multi-Disciplinary Obstetric Team Decreases the Mortality Rate of Pregnant Women with Sickle Cell Disease in Ghana

Prospective Implementation of Multi-Disciplinary Obstetric Team Decreases the Mortality Rate of Pregnant Women with Sickle Cell Disease in Ghana

Leveraging ongoing research to evaluate the health impacts of South Africa's salt reduction strategy: a prospective nested cohort within the WHO-SAGE multicountry, longitudinal study

IntroductionAttempting to curb the rising epidemic of hypertension, South Africa implemented legislation in June 2016 mandating maximum sodium levels in a range of manufactured foods that contribute significantly to population...

On the Same Page—Physicist and Radiologist Perspectives on Protocol Management and Review

To sustain compliance with accreditation requirements of the ACR, Joint Commission, and state-specific statutes and regulatory requirements, a CT protocol review committee requires a structure for systematic analysis of protocols. Safe and reproducible practice of CT in a complex environment requires that physician supervision processes and protocols be precisely and clearly presented. This article discusses necessary components for data structure, and a description of an IT-based approach for protocol review based on experiences at 2 academic centers, 3 community hospitals, 1 cancer center, and 2 outpatient clinics.

Hispanic accrual on randomized cancer clinical trials: a call to arms.

Hispanic accrual on randomized cancer clinical trials: a call to arms.

Establishment and validation of a pre‐clinical, multi‐center, multi‐species consortium for the assessment of infarct size‐reducing agents: CAESAR (Consortium for the preclinicAl assESsment of cARdioprotective therapies) (LB698)

Despite decades of effort and staggering financial support, the cardioprotection field failed to deliver a drug that effectively reduces infarct size in patients. To address the limitations to such preclinical studies and promote progress in this critical area of medical research, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR). The first step for CAESAR’s validation involved testing the “gold standard” for infarct size limitation: ischemic preconditioning (IPC). CAESAR tested the capacity for IPC to reduce infarct size in three species (at two sites/species): mouse (n=22‐25/group), rabbit (n=11‐12/group), and pig (n=13/group). During this validation phase, we confirmed that IPC significantly (p&lt;0.05) reduced infarct size in all species, and, successfully established a multi‐center structure to support CAESAR’s operations, including: two distinct surgical centers for each species, a pathology core (to assess infarct size), a biomarker core (to assess cardiac protein release into blood), and a data coordinating center ‐ all with the oversight of a protocol review and monitoring committee of distinguished experts. Such an infrastructure promotes careful, blinded, randomized, statistically sound, and rigorous evaluation of cardioprotective agents. Thus, CAESAR is operational and represents a new approach to pre‐clinical cardioprotection studies.Grant Funding Source: Source of Support: National Institutes of Health (NIH)‐Heart Lung and Blood Institute (NHLBI) CAESAR Consortium‐U24 HL094373

Hiv-1 infection and highly active anti-retroviral therapy effect on lipid metabolism in ghanaian patients

To investigate the impact of HIV-1 infection and highly active anti-retroviral therapy on lipid metabolism in Ghanaian patients. A total of 60 HIV-1-infected patients on highly active anti-retroviral therapy and 18 HIV-naive were age-matched with 45 sero-negative normal healthy volunteers. Participants demographic and clinical data were obtained from medical records and well-structured questionnaire after consented. Healthy individuals with lipid disorder were excluded from the study. Serum lipids were determined following standard protocols. The study was approved by the University of Ghana, School of Allied Health Sciences, Ethical and Protocol Review Committee. Most frequent combined therapy used was nucleoside analogue reverse transcriptase inhibitors. Married individuals (61.7%) were almost as twice as the singles receiving treatment. Body mass index, waist-to-hip ratio, diastolic and systolic blood pressures were significantly raised in patients on highly active anti-retroviral therapy than naive and healthy volunteers. Total cholesterol and TG were significantly elevated in patients on highly active anti-retroviral therapy treatments than naive group and volunteers (p < 0.001). Patients on treatment and naive group showed significantly raised LDL-C and VLDL-C with increased cardiovascular risk index than NHV (p < 0.01). High density lipoprotein level decreased in the patient on HAART and naive group than the volunteers (p < 0.05). Serum lipids were elevated in HIV-1 infected individuals but more pronounced in patients receiving highly active anti-retroviral therapy and may suggest an increased risk of cardiovascular disease in the patients.

The Implementation and Evaluation of an Evidence-based Statewide Prehospital Pain Management Protocol Developed using the National Prehospital Evidence-based Guideline Model Process for Emergency Medical Services

Background. In 2008, the National Highway Traffic Safety Administration funded the development of a model process for the development and implementation of evidence-based guidelines (EBGs) for emergency medical services (EMS). We report on the implementation and evaluation of an evidence-based prehospital pain management protocol developed using this model process. Methods. An evidence-based protocol for prehospital management of pain resulting from injuries and burns was reviewed by the Protocol Review Committee (PRC) of the Maryland Institute for Emergency Medical Services Systems (MIEMSS). The PRC recommended revisions to the Maryland protocol that reflected recommendations in the EBG: weight-based dosing and repeat dosing of morphine. A training curriculum was developed and implemented using Maryland's online Learning Management System and successfully accessed by 3,941 paramedics and 15,969 BLS providers. Field providers submitted electronic patient care reports to the MIEMSS statewide prehospital database. Inclusion criteria were injured or burned patients transported by Maryland ambulances to Maryland hospitals whose electronic patient care records included data for level of EMS provider training during a 12-month preimplementation period and a 12-month postimplementation period from September 2010 through March 2012. We compared the percentage of patients receiving pain scale assessments and morphine, as well as the dose of morphine administered and the use of naloxone as a rescue medication for opiate use, before and after the protocol change. Results. No differences were seen in the percentage of patients who had a pain score documented or the percent of patients receiving morphine before and after the protocol change, but there was a significant increase in the total dose and dose in mg/kg administered per patient. During the postintervention phase, patients received an 18% higher total morphine dose and a 14.9% greater mg/kg dose. Conclusions. We demonstrated that the implementation of a revised statewide prehospital pain management protocol based on an EBG developed using the National Prehospital Evidence-based Guideline Model Process was associated with an increase in dosing of narcotic pain medication consistent with that recommended by the EBG. No differences were seen in the percentage of patients receiving opiate analgesia or in the documentation of pain scores.

Improving Patient Care Through Interprofessional Education

Abstract 4764For interprofessional healthcare teams to succeed, collaborative learning should foster an understanding of the value of each profession for improving patient outcomes. Center of Excellence Media, LLC is conducting independent follow-up research to investigate how barriers to optimal patient care can be addressed through comprehensive education with interprofessional-targeted application directives. In addition, it is examining whether activities that recognize each team member's roles and responsibilities can foster interprofessional communication.Considerations in Multiple Myeloma™ and Considerations in Lymphoma™ are two annual series of CME/CE accredited activities that provide clinicians with information they need to make up-to-date and appropriate treatment decisions for their patients, and are simultaneously made available as supplements to the professional publications The Oncology Nurse-APN/PA®, The Oncology Pharmacist®, and Value-Based Cancer Care®. The faculty panel for each activity is comprised of a hematologist-oncologist, a midlevel provider (a nurse, nurse practitioner, or physician assistant), and a pharmacist from a leading cancer institution, which allows added insight into an interprofessional approach to care. Following a successful didactic series in 2009, in which faculty members discussed their professional perspectives of evidence and data, the 2010 series was case-based and contained commentary from faculty describing their individual roles in patient management. The 2011 series, entitled “Ask the Experts,” poses frequently asked questions regarding the management of myeloma or lymphoma to faculty panels.Preliminary findings have shown that participants have become more aware of the roles and responsibilities of other healthcare professionals (98.5%), and are more comfortable interacting with other members of their practice after participating in these activities (97.8%). They are also collaborating more with other professionals involved in the treatment of their patients (89.3%). Not only were participants individually better able to care for patients after participating in these activities (98.2%), they also acknowledged that interprofessional patient care had been enhanced (97.8%). We continue to collect follow-up data as new activities in this series are released; comprehensive data will be presented at the ASH Annual Meeting. Disclosures:Gregory:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech (Roche): Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; GlaxoSmithKline: Research Funding; Immunomedics: Research Funding; Onyx: Research Funding. Kaufman:Millennium: Consultancy; Celgene: Research Funding; Keryx: Protocol Review Committee; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

Preface for JCOG Review Series

JCOG (Japan Clinical Oncology Group) was started in 1990 and is the only governmental clinical trial group in Japan. The ultimate purpose of JCOG is to establish gold standard therapies for each tumor type based on scientifically and ethically scheduled investigator-initiated clinical trials. JCOG is composed of various committees for auditing and management, a data center and clinical study groups. The steering committee meeting is held four times a year and decides the missions, principles and policies of JCOG, the exchange of JCOG members and the approval of practical protocols for clinical trials. JCOG has 15 study groups and about 170 member institutions and hospitals. The number of nominated institutions is limited to keep high quality of JCOG. Inactive institutions have been replaced with other institutions by the steering committee. The number of patients accrued for each clinical trial is influenced by the number of active protocols in each trial group. Some groups are very active, while others have not yet completed any trials. JCOG conducts only investigator-initiated trials and so far has not been involved in any IND (Investigational New Drug) trials. Because JCOG does not receive any funding from pharmaceutical companies, the data are not biased by conflicts of interest. Since 1978, JCOG has conducted 216 clinical trials, the majority of which were Phase III trials. The results have been presented at regional and international scientific meetings and have been reported in mainly English language journals as original articles. Some have been published in journals with high impact factors, such as the New England Journal of Medicine, the Journal of the National Cancer Institute, and the Journal of Clinical Oncology. In addition to the evaluation of new anticancer drugs, radiation therapy and new surgical procedures have also been tested in randomized controlled trials. Extremely important data have been published by surgical groups. Some clinical trials have produced positive results, but others did not achieve their primary endpoints. In addition, the accrual of patients was sometimes so poor that the clinical trial had to be interrupted. In a few studies, an independent data monitoring committee suggested that patient accrual be stopped because of the high incidence of severe toxicity arising from treatment and unexpected negative or inverse results. Recently, the publication of such data has become extremely difficult because of the rapid increase in articles that are being submitted to popular journals. The editors of such journals have suggested that the rejection rate should be as high as 80–90% and that ‘Me too-type’ articles with no significant data and single-arm Phase II studies of standard therapy should be rejected because the cost of publication is becoming too high and too many articles are waiting for publication. As a result of this situation, data concerning negative results or interrupted clinical trials are often difficult to publish. Nevertheless, such information is very important to young active investigators who are developing new protocols for clinical trials. JCOG has a policy that the outcome of a clinical trial should be published in English once it has been approved by the protocol review committee. The Japanese Journal of Clinical Oncology has agreed to publish review articles for each clinical trial group, enabling ‘hidden data’ to become available. Consequently, the chairman of each group in JCOG has been asked to write a review article on their study group. In each review, the author has included all the clinical trials within their group that have been approved by the protocol review committee of JCOG. Readers should be able to recognize the development/refinement of each study group and understand the reasons for negative results and low patient accruals as well as the unexpected early termination of studies. Readers will also be able to understand the success rate of clinical trials. To complete each clinical trial, numerous specialists must join and collaborate with one other. Therefore, clinical trials with negative results and with low accruals should be avoided as much as possible. This series will provide important information regarding the writing of proper clinical protocols for clinical trials. The first review is written by Dr Takashi Onda, Gynecologic Oncology Division of National Cancer Center, on behalf of the chairman of the gynecological group. The group has published four articles reporting the results of the JCOG9412, 0206, 0602 and 0505 trials in the Int J Gynecol Cancer, Gynecol Oncol, Jpn J Clin Oncol and Jpn J Clin Oncol, respectively. Additionally, JCOG0102 and 0503 are introduced in the review article.

Development time of trial protocols in the Japan Clinical Oncology Group (JCOG).

e16568 Background: Protocol development process consists of multiple steps and takes considerable amount of time, and it is regarded as one of barriers for timely trial completion. Streamlining of protocol development has been one of the major concerns worldwide today. Dilts et al. reported that median calendar days to activate phase III trial are 784 in CALGB (JCO 2006), 808 in ECOG (Clin Cancer Res 2008), and 602 in all CTEP-sponsored trials (JCO 2009). We studied protocol development time of the trials conducted by JCOG and explored possible solutions for streamlining protocol development. Methods: An analysis for protocol development time was conducted on all JCOG trials activated between 2000 and 2010. Protocol development time was the calendar time from concept approval by JCOG Executive Committee to final protocol approval by JCOG Protocol Review Committee. Association between “fast/slow,” divided by median, and trial characteristics were investigated by both univariate comparison and multivariate logistic regression analysis. Results: The median protocol development time was 573 days in 69 trials (range: 222 to 2,413 days). The results of subset analyses are shown in the table. Variability was remarkable among disease subgroups and year of concept approval. Odds ratio (OR) in multivariate logistic regression model was significant only in disease subgroups (faster in gastrointestinal group). Conclusions: Unfavorably, it took longer time in phase II trials than in phase III trials, and more time may have been needed to reach agreement on protocol treatment among investigators in phase II. To reduce intergroup difference, more aggressive promotion of sharing know-how in faster disease group may be necessary. Protocol development time by trial characteristics. N Median (days) Year of concept approval 2000-2001 17 551 2002-2003 17 432 2004-2005 15 879 2006-2007 12 697 2008-2009 8 481 Phase II 18 690.5 III 32 533.5 Modality Chemotherapy alone 23 573 Radiotherapy included 14 481 Chemoradiotherapy included 7 752 Surgery included 28 578.5 Group Gastrointestinal groups 30 519.5 Lung groups 14 598.5 Other disease groups 25 653

Experiences of Institutional Review Board (IRB) and Protocol Review and Monitoring Committee (PRMC) Rotations in Hematology/Oncology Training

Trainees in hematology oncology need to learn development and regulation of clinical research protocols. We hypothesized that rotation on the Institutional Review Board (IRB) and Protocol Review and Monitor Committee (PRMC) at our university could improve fellows' understanding of clinical trial development and regulation. Since 1999, 20 fellows in our training program have rotated through either IRB or PRMC for 3 months. We evaluated their experiences by anonymous questionnaire with 13 quantitative, 1 yes-or-no, and 4 open-ended questions and correlated responses to their demographic characteristics. We report here these fellow's experiences in attending these meetings. We also describe other benefits of IRB/PRMC participation in training fellows, and finally propose to other fellowship programs to consider this educational approach as a way of enhancing hematology/oncology training.

Scientific review of EORTC trials: the functioning of the New Treatment Committee and Protocol Review Committee

New anticancer treatments (new therapeutic strategies or new compounds) require careful development in which cancer clinical trials are an essential element. Two scientific committees, namely the New Treatment Committee and the Protocol Review Committee, ensure the review of all EORTC protocols with respect to the interest and originality, methodology, feasibility and relevance within the EORTC framework. Both Committees are involved early in the evaluation of the new concept proposal and follow all aspects (methodology, administrative, regulatory) of the protocol development process. Throughout its 25 years of existence, the Protocol Review Committee has streamlined drug and protocol evaluations and has developed standard operating procedures to handle those reviews in a very efficient and fast manner. Since 1997, the New Treatment Committee has contributed to strengthening the EORTC during the development process with the aim of ensuring an optimal flow of information on new drugs between laboratory and clinical research divisions.

Phase II trials in the EORTC

The Protocol Review Committee (PRC) has prepared this document in order to clarify the phases of introduction of a new therapeutic agent in the treatment of cancer. Our aim is to define these phases and to make explicit the intentions which lie behind EORTC studies at each stage in the process. The PRC hopes that this will help the Cooperative Groups of the EORTC in developing their protocols for clinical trials carried out under the auspices of the EORTC. This position paper may also assist those undertaking this form of clinical research outside the EORTC.