WHAT IS NEW AT NIH & OTHER UPDATES October 25, 2017 Frances Payne Bolton School of Nursing Center for Research & Scholarship https://sites.google.com/a/case.edu/new-at-nih_10-25-17/ Summary of NIH Changes: 12.7.16 - 1.25.18 Effective Topic Date Summary of Change Website 1. Need to ensure that you https:// follow guidelines for clinical grants.nih.gov/policy/clinical-trials/CT-decision-tree.p trial. (Answer 4 questions). df 2. Can only submit Clinical Trial Definition & https:// Specific Application 25-Jan-18 applications involving clinical grants.nih.gov/grants/guide/notice-files/NOT-OD-17trials if the specific RFP or (NOT-OD-17-043) 043.html FOA specifically calls for clinical trials.

https://clinicaltrials.gov/ct2/manage-recs/how-regist er Clinical Trials: New Review Criteria 25-Jan-18 Additional review criteria for https://grants.nih.gov/grants/guide/notice-files/NOTOD-17-118.html clinical trials (NOT-OD-17-118) Expansion and use of discrete https:// form fields for clinical trial grants.nih.gov/policy/clinical-trials/new-human-subje ct-clinical-trial-info-form.htm information New NIH "FORMS-E": Clinical Trials 25-Jan-18 https:// (NOT-OD-17-062) grants.nih.gov/grants/ElectronicReceipt/files/Annotat ed_Forms_General_FORMS-E.pdf New NIH "FORMS-E": Human Subjects (NOT-OD-17-062) 25-Jan-18 Consolidation of human subjects, inclusion enrollment, and clinical trial information.

https:// grants.nih.gov/policy/clinical-trials/new-human-subje ct-clinical-trial-info-form.htm https:// grants.nih.gov/grants/ElectronicReceipt/files/Annotat ed_Forms_General_FORMS-E.pdf DEFINITION OF A CLINICAL TRIAL Summary of NIH Changes: 12.7.16 - 1.25.18 Effective Topic Date Summary of Change Website All information required for https://grants.nih.gov/grants/guide/notice-files/NOT -OD-17-098.html the peer review process must be contained within those designated sections Elimination of Appendix for Clinical of the application image, Trials Applications 25-Jan-18 unless the FOA specifies (NOT-OD-17-098)

otherwise. NIH Policy on the Dissemination of NIHFunded Clinical Trial Information (NOT-OD-16-149) All NIH-funded clinical trials are expected to register and submit results information to 18-Jan-17 Clinicaltrials.gov. https://clinicaltrials.gov/ct2/home Topic Policy on Post-Submission Materials (NOT-OD-17-066) Issuing Certificates of Confidentiality (NOT-OD-17-109) Appendix Policy

(NOT-OD-17-035) Summary of NIH Changes: 12.7.16 - 1.25.18 Effective Date Summary of Change Website https://grants.nih.gov/grants/guide/notice-files/ NOT-OD-17-066.html Post-submission materials are submitted after submission of the 25-Sep-17 grant application but prior to initial peer review. They are not intended to correct oversights or errors discovered after submission. See website for complete list of materials. https://grants.nih.gov/grants/guide/notice-files/ NOT-OD-17-109.html 17-Sep-17 Certificates automatically apply to all funded studies. Special policy for clinical trials. For https://grants.nih.gov/grants/guide/notice-files/ NOT-OD-17-035.html other applications, ONLY blank consent forms, blank surveys and/ or data collection instruments. If your application DOES NOT meet

25-Jan-17 these criteria, it will be deemed to be ineligible. Summary of NIH Changes: 12.7.16 - 1.25.18 Topic Effective Date Summary of Change All NIH-funded investigators and Good Clinical Practice (GCP) Training: Clinical Trials 16-Sep-16 staff who are involved in the conduct, oversight, or (NOT-OD-16-148) management of clinical trials should be trained in GCP. Society of Behavioral Medicine: Good, easy to use, practical site. RECOMMENDED SITES FOR 16-Sep-16 CITI site more complex but you GCP Training can get CREC credits. Rigor and Transparency

Sex as a Biologic Variable For most research grants and RPPRs, application requirements aim to enhance reproducibility of 25-Jan-16 research findings through increased scientific rigor and transparency. Explain how relevant biological variables are factored into research designs & analyses. Website https:// grants.nih.gov/grants/guide/notice-files/NOT-OD-16 -148.html https://osp.od.nih.gov/clinical-research/clinical-trial s/ http:// www.sbm.org/training/good-clinical-practice-for-so cial-and-behavioral-research-elearning-course https ://about.citiprogram.org/en/series/good-clinical-pra ctice-gcp/ https://

grants.nih.gov/grants/peer/guidelines_general/Revi ewer_Guidance_on_Rigor_and_Transparency.pdf https://grants.nih.gov/reproducibility/index.htm https://grants.nih.gov/grants/guide/notice-files/NO T-OD-15-102.html h ttps://grants.nih.gov/grants/peer/guidelines_gener al/SABV_Decision_Tree_for_Reviewers.pdf Rigor & Reproducibility 1. Scientific Premise 2. Scientific Rigor (Design) 3. Biological Variables (SABV) 4. Authentication

4 AREAS OF FOCUS WHAT DOES SCIENTIFIC RIGOR MEAN? Scientific Premise The scientific premise for an application is the research that is used to form the basis for the proposed research question(s). Describe the general strengths and weaknesses of the prior research being cited as crucial to support the application. Consider discussing the rigor of previous experimental designs, as well as the incorporation of relevant biological variables and authentication of key resources. Scientific Rigor (Design) Scientific rigor is the strict application of the scientific method to ensure robust and unbiased experimental design, methodology, analysis, interpretation and reporting of results. Emphasize how the experimental design and methods proposed will achieve robust and unbiased results.

WHERE SHOULD IT BE INCLUDED IN THE APPLICATION? Research Strategy Significance Research Strategy Approach 4 AREAS OF FOCUS Biological Variables WHAT DOES IT MEAN? Biological variables, such as sex, age, weight, and underlying health conditions, are often critical factors affecting health or disease. In particular, sex is a biological variable that is frequently ignored in animal study designs and analyses, leading to an incomplete understanding of potential sex-based differences in basic biological function, disease processes and treatment response. Explain how relevant biological variables, such as the ones noted above, are

factored into research designs, analyses, and reporting in vertebrate animal and human studies. Strong justification from the scientific literature, preliminary data or other relevant considerations must be provided for applications proposing to study only one sex. Sex as a Biologic Variable WHERE SHOULD IT BE INCLUDED IN THE APPLICATION? Research Strategy Approach NIH Review Criteria: Evaluate https://grants.nih.gov/grants/peer/guidelines_general/SABV_Decision_Tree_f adequacy of research plan or_Reviewers.pdf with regarding to SABV 4 AREAS OF FOCUS WHAT DOES IT MEAN?

WHERE SHOULD IT BE INCLUDED IN THE APPLICATION? Key biological and/or chemical resources include (but are not limited to) cell lines, specialty chemicals, antibodies, and other biologics. Authentication Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the studies. These resources may or may not be generated with NIH funds and: Other Research Plan May differ from lab to lab over time May have qualities and/or qualifications that could influence the research Section: data Include as an attachment Are integral to the proposed research Do not include in the The authentication plan should state in one page or less how you will Research Strategy authenticate key resources, including the frequency, as needed for your research. Examples: https://www.uab.edu/ccts/images/R2T_Appendix_Documents/Pollock_Auth

entication_Appendix.pdf Summary of NIH Changes: 12.7.16 - 1.25.18 Topic Effective Date Summary of Change For research grants, use of a Authentication of Key new "Authentication of Key Biological and/or Chemical 25-May-17 Biological and/or Chemical Resources Resources" attachment (NOT-OD-17-068) Website https:// grants.nih.gov/grants/guide/notice-files/NOT-OD-17-068 .html All investigators funded by NIH submit or have submitted to https://publicaccess.nih.gov/policy.htm

the National Library of Medicine's PubMed Central, NIH Public Access Policy an electronic version of their https://grants.nih.gov/grants/guide/notice-files/NOT-OD(NOT-OD-15-091) 15-091.html final, peer-reviewed 18-Mar-14 manuscripts upon acceptance -Public Access Policy https://www.ncbi.nlm.nih.gov/pmc/about/submissionfor publication, to be made Progress Reports publicly available no later than methods/ -How Papers Get into PMC 12 months after the official https://www.nihms.nih.gov/db/sub.cgi? date of publication. process_auth=1&login=myNCBI Data and Safety Monitoring Plans -Definitions, Guidelines -Templates for DSMB/C A separate attachment to https:// emphasize the importance www.nia.nih.gov/research/dgcg/clinical-research-study-i nvestigators-toolbox/data-and-safety-monitoring

and facilitate systematic 25-May-16 enforcement of the Data and Safety Monitoring Plan. NEW NIH MECHANISMS New Mechanism Description Websites R34 (PAR-17-133) Applications that propose the complete planning, design, and preparation of the documentation necessary for implementation of investigatorinitiated clinical trials. The application should propose the developmental work to be performed that would enhance the probability of reaching definitive outcomes in a clinical trial. Supports planning for clinical trials that address high-priority research questions related to the mission and goals of the funding agency. Sufficient pre-clinical data to support the planning of the clinical trial should be available prior to

submission of the R34 grant application. The proposed trials should be hypothesis-driven and milestone-defined. https://grants.nih.gov/grants/guide/pa-files/P AR-17-133.html https://grants.nih.gov/grants/peer/r_awards/ R34_guide_for_reviewers.pdf NEW NIH MECHANISMS New Mechanism Description Websites R61/R33 (PAR-16-405) https://grants.nih.gov/grants/guide/ Supports applications to develop and implement phase II pa-files/PAR-16-405.html and beyond investigator-initiated single-site clinical trials. Applications must be relevant to the research mission of the NHLBI and meet the NIH definition of a clinical trial.

http://www.nhlbi.nih.gov The award is bi-phasic and milestone-driven. Applications must present the scientific rationale for the clinical trial and a comprehensive scientific and operational plan that describes the conduct of the trial, as well as plans for project management, subject recruitment and retention, performance milestones, scientific conduct of the trial, and dissemination of results. The multiple PD/PI model is strongly encouraged but not required. Applicants are encouraged to include a PD/PI with expertise in biostatistics, clinical trial design, and coordination. UPDATES: Data Use AgreementCWRU Key Aspects Description What is a data use agreement (DUA)? A Data Use Agreement (DUA) is a contractual document used for the transfer of data that have been developed by nonprofit, government or private industry, where the data are nonpublic or are subject to some restrictions on its use. When is a DUA

needed? When a member of a research team leaves CWRU or the research team wishes to have access to the data which belongs to CWRU. When an individual who is not an employee of CWRU requests access to and use of the data which belongs to CWRU. Who manages the DUAs at CWRU? Technology Transfer Office at CWRU. Current contact person: Andy Jarrell at 368-1401 or [email protected] What are the steps of submitting DUA? Complete & submit a DUA Review Form to Technology Transfer (See Google Site) Technology Transfer composes the actual agreement & obtains approval from CWRU legal Obtain needed signatures Issues to Consider Different considerations if data are de-identified vs not de-identified Need clear understanding of where data are currently housed & where data by requesting individual will be housed Need clear understanding of what requested data will be used for

TRAINING SLIDES FOR NIH REVIEWERS ARE ATTACHED TO ADD ADDITIONAL CLARIFICATION REGARDING SCORING CRITERIA FOR NIH GRANTS CSR Core Reviewer Training Slides August 19, 2017 Training Resources Committee Dr. Karyl Swartz, Chair Overall Impact and Significance Overall Impact is the likelihood for the project to exert a sustained, powerful influence on the research field. Evaluation is driven by the importance of the problem in the field. Overall Impact can be influenced by all five scoreable criteria (significance, investigator, innovation, approach, environment) and score-driving criteria, prioritized according to reviewer judgment. Significance is a key score-driving review criterion that evaluates the potential effect on the field if the aims are SUCCESSFULLY completed. Evaluate if project is based on a strong premise, or scientific foundation. Assuming successful completion of aims, evaluate how much the project will move the field forward. Describe specific advancement in knowledge, technology, or clinical practice that

the project will bring, NOT the importance of the topic, field, or disease. 6 An application need not have a direct link to health nor be hypothesis-driven to have significance Note: Mission of NIH includes basic & clinical research Examples of projects with potential high significance and high overall impact: studies of fundamental properties of basic biological processes without any translational aim projects that study rare diseases projects that use in silico, in vitro, or in vivo models (cell lines, invertebrate or vertebrate animal models, or human subjects) non-hypothesis driven, exploratory studies technological, methods development, models creation, data analytic and analytic methods development efforts data collecting, cataloguing, cohort building or other resource development projects 7 Other Scored Criteria Investigator(s): evaluate productivity of the investigators in terms of impact of their work on the field, not just by number of publications or the impact factor of the journals evaluate PIs ability to lead a major project but not their independence a collaboration should be supported by a letter and/or a history of previous collaboration, not necessarily by requesting budget support

Innovation: conceptual and/or technological use of appropriate methodology that may not be innovative is not a weakness Approach: address scientific rigor and relevant biological variables including sex evaluate whether strategy, methods and preliminary data support feasibility consider whether pitfalls and alternative strategies are discussed Environment: evaluate if the specific resources available are appropriate for the needs of the project, not the prestige of the institution 8 Rigor and Reproducibility Rationale: To support the highest quality of research, public accountability, and social responsibility in the conduct of science, scientific community makes a special effort to advance rigor in designing and performing research and the ability to reproduce biomedical research findings. NIHs Rigor and Reproducibility policy clarifies expectations and highlights four areas that need more explicit attention by applicants and reviewers. 1. Scientific Premise is the scientific foundation of the project, including the quality and strength of prior research. As defined by NIH, premise is distinct from a hypothesis or justification; it is a retrospective consideration of the foundation for the application. Under Significance, explain how specifically the underlying preliminary data and/or published literature support the scientific question (score-driving). Needs to be a scientific justification if both sexes are NOT included. State whether data will be disaggregated by sex or other biologic variables. 2. Scientific Rigor is the strict application of the scientific method that supports robust and unbiased approach in design, analysis, interpretation, and reporting of results. Sufficient information should be

provided for the study to be assessed and reproduced. Animal numbers and other statistics should be included in the Research Plan. Scientific Rigor is addressed under Approach (score-driving). 9 Rigor and Reproducibility 3. Relevant Biological Variables, including sex: all studies involving human subjects or vertebrate animals should account for sex and other relevant biological variables (age, source, weight, or genetic strain). Should be explicitly addressed under Approach (score-driving). State whether humans and/or vertebrate animals of both sexes are included If only one sex is being used, state whether and how this is scientifically justified. Cost, absence of known sex differences, aggressiveness of male mice are not adequate justifications State whether the data will be disaggregated according to sex and other biological variables 4. Key biological and/or chemical resources: cell lines, specialty chemicals, antibodies and other biologics that may differ from laboratory to laboratory or over time. Provide specific evaluation of the processes used to validate quality of key resources to avoid unreliable results This is a non score-driving review consideration addressed in separate section of critique, but severe concerns may affect Approach 10 Human Subjects Protections and Inclusions: Score-Driving Regardless of whether application designates Yes or No for Human Subjects, evaluate whether human

subjects are involved and whether exemptions may apply. If research involves human subjects (but does not qualify for IRB Exemptions), evaluate four points: the risk to subjects the adequacy of protection against risk potential benefits of the research to subjects and others the importance of the knowledge to be gained If the application proposes a clinical trial, consider if the application describes an appropriate Data and Safety Monitoring Plan. (*NIH has its own definition of clinical trial). Can be in Human Subjects section. Secondary data analyses are usually considered as Human Subjects research. Need data use agreements. If claiming an exemption, then need to include details/process regarding how they will de-identify data. If research involves human subjects (but does not qualify for IRB Exemptions), evaluate if the proposed inclusion of women, minorities, and children under 18 years of age is scientifically justified. 11 Vertebrate Animals and Biohazards: Score Driving For any proposed use of live vertebrate animals, comment on four points: description of procedures, including species, strains, ages, sex, and total number of animals (justification of animal numbers is now part of Research Plan) justification for the choice of species minimization of pain and distress

method of euthanasia is now included in the PHS form D Cover Page Supplement; if not consistent with the recommendations of the AVMA Guidelines for the Euthanasia of Animals, a description and scientific justification of the method should be provided in the text box Biohazards are research components known in the professional community to pose a risk to research personnel and/or the environment (biological organisms, toxins, radioactivity, dangerous chemicals, or recombinant DNA). Applications do not contain a separate section on Biohazards. They can be addressed throughout the application, including the Facilities section Determine whether proper handling procedures and adequate protections are addressed (personnel training, safety protocols, containment facilities, waste disposal) 12 Resubmission and Renewal: Score Driving Resubmission (A1) is an unfunded application that has been modified following initial review and resubmitted for new consideration. Evaluate & Score the application presented. Comment on the quality of changes made in response to the initial review (summarized in Introduction). Have they addressed prior concerns sufficiently or are there still issues? Current score should not be influenced by the score from the previous submission Renewal is an application requesting additional funding for a period subsequent to that provided by the current award. Evaluate progress made in the last period of support, not necessarily by publications in high impact journals, but in terms of achieving the previous goals and the impact this has had on the field 13

Assigned reviewers should evaluate and comment on Additional Non Score-Driving Review Considerations Applications from Foreign Organizations evaluate if other countries present special opportunities not available in the US Select Agents are hazardous materials that pose a severe threat to public as listed by DHHS (not general Biohazards) Resource Sharing Plans relate to unique developed tools such as model organisms or genomic data. If budget >$500K for one year or using Genomic dataa resource sharing plan is required to share information with other researchers. Should reviewers be concerned if this is developing something that could be commercialized? Is there a plan to share this app (or commercialized product) with other PIs. Authentication of Key Biological and/or Chemical Resources. Needs to be authentication (biologic variables)especially if not using a kit. Budget and Period of Support if proposing changes in time or amount, make specific recommendations, and comment on potential overlap 14 Evaluating Overall Impact Overall Impact: The likelihood for a project to exert a sustained, powerful influence on research field(s) involved

Evaluating Overall Impact: Consider the 5 criteria: significance, investigator, innovation, approach, environment (weighted based on reviewers judgment) and other score influences (e.g. human subjects) Overall Impact High Score 1 2 3 e.g. Applications are addressing a problem of high importance/interest in the field. May have some or no weaknesses.

Medium Low 4 5 6 7 8 9 e.g. Applications may be addressing a problem of high importance in the field, but weaknesses in the criteria bring down the overall impact to medium. e.g. Applications may be addressing a problem of moderate importance in the field, with some or no weaknesses. e.g. Applications may be addressing a

problem of moderate/high importance in the field, but weaknesses in the criteria bring down the overall impact to low. e.g. Applications may be addressing a problem of low or no importance in the field, with some or no weaknesses. 5 is a good medium-impact application, and the entire scale (1-9) should always be considered. 15

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