Clinical Research Grants - PowerPoint Presentation

1. Clinical Research Grants-differences from Basic Research-Tetsuo Ashizawa, M.D.

2. NIH definition of clinical researchResearch with human subjects that is:Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. It includes:mechanisms of human diseasetherapeutic interventionsclinical trialsdevelopment of new technologiesEpidemiological and behavioral studies.Outcomes research and health services research.

3. Research that does not involve research on human subjects, and is devoted to discovery of biological processes and/or disease mechanisms.Under this definition, Basic Research excludes: a) All research on potentially identifiable human subjects (e.g., clinical trials) b) Therapeutic and/or diagnostic development. NIH definition of basic research

4. NIH Definition of Clinical TrialA prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective.Phase I. Tests a new biomedical intervention in a small group of people (e.g. 20-80) for the first time to determine efficacy and evaluate safety).Phase II. Study in up to several hundred people to determine efficacy and further evaluate safety.Phase III. Study to determine efficacy in large groups of people (up to several thousand) and to collect information that will allow the interventions to be used safely.Phase IV. Studies conducted after the intervention has been marketed.

5. Exemptions from coverage by the human subjects regulationsExemption 1: Instructional strategies in established educational settingsExemption 2: Educational tests unlinkable to individuals and no risks from disclosureExemption 3: Educational tests on public officials, or absolute federally mandated confidentialityExemption 4: Existing data/specimens, publicly available, unlinkable to individualsExemption 5: Demonstration projects concerning public benefit or service programsExemption 6: Taste and quality evaluation of foods without additives exceeding regulated levels

6. Mechanisms of NIH FundingResearch Grant: R01, R03, R21, R23, R00Clinical Trial Planning Grant: R34 Cooperative Agreement Grant: U01 (Research Project), U10 (Cooperative Clinical Research), U54 (Specialized Center)Small Business Grant: R41/R42 (STTR), R43/R44 (SBIR)Career Development Grant: K01, K08, K22, K23, (K25), K99/R00 (mentored); K02, K24 (independent career development)Research Program Project Grant: P01 (Program Project), P20, P30 (Center Core), P50 (Center)Resource-Related Research Project Grant: R24Resource Access Program Grant: X01Institutional Training Programs: T32, K12, R25, Individual Pre/postdoctoral: F31, F32, F33

7. Funding Opportunity Announcement (FOA)Program Announcement (PA)Usually accepted on standard receipt dates on an on-going basisRemains active for 3 years Includes PAR (with special receipt, referral and/or review considerations) and PAS (with specific set-aside funds)Request for Application (RFA)Usually has a single receipt dateProposals submitted for RFA can be re-submittedfor PA!

8. Translational ResearchBasic Research Grant Basic ResearchR/U/P/X/STTR grants Phase I/II/III Clinical TrialsExploratory/Developmental Projects Preclinical preparation for IND, IDE, or 510(K) in Translational Research (R21) STTR (R41) and SBIR (R43) Tech innovation, transfer and commercialization

9. Also see: http://grants.nih.gov/grants/guide/index.html http://fundingopps.cos.com/ https://www.grantforward.com/index

10. HOMEABOUT GRANTSFUNDINGFORMS &DEADLINESFUNDINGGRANTS POLICYGrants & Funding

11. NINDS Exploratory/Developmental Projects in Translational Research (R21) PAR-13-023To support any research activities required to advance candidate therapeutics through Investigational New Drug (IND), Investigational Device Exemption (IDE), or 510(K) submission to the Food and Drug Administration (FDA), and ready them for clinical testing for neurological disorders. A strong biological rationale Supporting data from rigorously designed experimentsProposed studies to exhibit methodological rigorOutcome expected to lead directly to or support another project (e.g. cooperative agreement in translational research) that will include all remaining activities for submission of an IND, IDE, or 510(k) application to the FDA$250K per year x 2 yearsClinical research, basic research, and studies of disease mechanism are outside the program scope.  

12. Small Business Innovation Research (SBIR)Small Business Technology Transfer (STTR) Public/private sector partnership to include the joint venture opportunities for small US business (<500 employees) and non-profit research institutionsR&D effort: Small business >40% and non-profit research institution >30% (STTR only)PI may be either from small business or non-profit for STTR and from small business only for SBIRTo bridge the gap between performance of basic science and commercialization of resulting innovationsTechnology innovationTechnology transferCommercialization of innovationsPhase I: to establish the technical merit, feasibility and commercial potential ($150K for 1yr)Phase II: to advance the successful STTR Phase I activities ($1M for 2yrs)Phase III: to pursue commercialization objectives resulting from STTR Phase I/II activities.**Available by only some STTR programs.

13. R34: NIH Clinical Trial Planning Grant ProgramSupports development of Phase III clinical trials. This program supportsestablishment of the research team,development of tools for data management and research oversightdefinition of recruitment strategies,finalization of the protocolpreparation of an operations/procedures manualNot to collect preliminary dataParent R34 Application Characteristicsa project period of one yeara budget for direct costs of up to four $25,000 modules or $100,000 per yearR34 Participating Institutes and Centers (PA-09-186): NIA, NIAAA, NIAMS, NICHD, NIDA, NEI, ODS

14. Writing Clinical Trial Grant ApplicationsIn principle, same as basic science grantsPreliminary data, approach – key differencesDesigns – PDBRPCStatisticsRationale Clinical trials: Equiposed?

15. Specific IssuesRead RFA, PA, FOA, etc. from cover to cover. Both PI and grant management office need to understand.Follow all the rules.Avoid rejection by the CSR – font, page limitations, format, margins and content.Determine IRB and other requirements.JIT and NOA.Do not expect any flexibility from CSR or reviewers.

16. Allow enough time for pre-review and revisions.

17. Common Elements and Importance from the Reviewer’s PerspectiveTitle and Face PageAbstractSpecific AimsSignificanceInvestigatorInnovationApproachEnvironmentHuman SubjectsVertebrate AnimalsBiohazardsBudget and Period of SupportSelect AgentsResource Sharing Plans

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19. Major Review Issues in National Institutes of Health Grant Proposals (n = 66)AreaSpecific aims/hypothesis ----------------------------------------------------------------Goals overstated, overly ambitious or unrealistic -------------------------------Poorly focused or inadequately conceptualized ---------------------------------Hypotheses not dearly articulated ---------------------------------------------------Background/Significance -----------------------------------------------------------------Need for study not well justified ------------------------------------------------------Too much background, insufficient room for methods, extraneous information ---------------------------------------------------------------------------------Overstatement of significance of study --------------------------------------------- From Inouye & Fiellin 2006Grants,n (%)30 (45)12 (18)10 (15) 8 (12)24 (36)19 (29) 3 (5) 2 (3)

20. AreaPreliminary/pilot studies ------------------------------------------------------- More pilot work needed ------------------------------------------------------- Studies cited with no clear link to proposed study ---------------------- Inadequate description of preliminary studies --------------------------Grants,n (%)33 (50)27 (41)4 (6)2 (3)Major Review Issues in National Institutes of Health Grant Proposals (n = 66)

21. Major Review Issues in National Institutes of Health Grant Proposals (n = 66)AreaMethods ------------------------------------------------------------------------------------------------Study patients ------------------------------------------------------------------------------------ Inclusion criteria (non-representative, bias, poor description) ----------------- Exclusion criteria (poor justification, overlooked, bias) --------------------------Data analysis (Poor statistics, no Intend-to-treat, unaddressed missing data) --Outcome (blinding, poor outcome measures, validity, omissions of variables) –Sample size/power (calculation, attrition rates) ------------------------------------------Controls --------------------------------------------------------------------------------------------Data collection/procedures -------------------------------------------------------------------Intervention (adherence monitor/analyses, randomization flaw, potency) --------Grants,n (%)66 (100)46 (70)36 (54)23 (35)42 (66)40 (66)28 (42)21 (32)18 (27)16 (24)

22. AreaGeneral Issues ---------------------------------------------------------------------Layout poor (editing/typographical/grammatical errors, inconsistencies, too-small font, omitted lines or tables, poor photocopy, difficult to read) -------------------------------------------------------Use of jargon, abbreviations, undefined terms ------------------------------Information presented in wrong sections -------------------------------------Limitations not adequately discussed (For revision) -----------------------Inadequately responsive to previous reviewers' comments -------------Grants,n (%)24 (36)13 (20)3 (5)3 (5)2 (3)5 (8)Major Review Issues in National Institutes of Health Grant Proposals (n = 66)

23. Understand the Reviewer’s PerspectiveThe reviewers are probably successful, busy researchers.They are “experts” but perhaps have little in-depth experience in your area of research.Except for the reviewers assigned to your application, study section members who vote their scores will have very limited time to review your application.KeyFocusConcisenessConceptual clarityTransparent languageCristal clear significanceAvoid jargonDefine acronymsSelf-contained No critical info in appendices

24. GrantFunded!

25. But first……Contact the program officer.Review successful grant applications of the type you will write.Check NIH Reporter (http://projectreporter.nih.gov/reporter.cfm) to avoid duplication.Take advantage of the Freedom of Information Act (FOIA) – www.nih.gov/icd/od/foia/coord.htm.Gauge the priorities of the funding agency.Know potential reviewers – study section roster www.csr.nih.gov/committees/rosterindex.aspGet advice from a biostatistician!

26. Specific Aims – the most important section – Hypothesis-driven vs needs-drivenGoalsSpecific AimsLong-term goalFocused? Underdeveloped?Overambitious?Input from mentors, colleagues and collaborators?Study design, sample size, study groups and primary outcomes included? i.e., no surprises to reviewers in later sectionAchieve answering the central hypothesis or the need if specific aims are accomplished?Specific aims complement one another but independent?Sound rationale for each aim?Clear hypothesis for each aim?Spend enough time on this page – i.e., until the time of submission

27. SignificanceThis section justifies and builds the case for the project.Say why the proposed project is needed.Encyclopedic background is a big “NO-NO” – keep it essential and relevant Each background sentence should link to the proposed project.Show how the proposed study builds on previous work.Identify knowledge gaps in previous knowledge and convince reviewers why the gaps need to be filled.Do not overstate the significance.Do not make it too long – other sections will run out of pages.Write with your maximal enthusiasm.

28. InnovationRemember that the NIH study section is not necessarily kind to totally innovative proposal – gap filling but with a certain boundary.“Your project should move the frontier of knowledge forward. Striving for a paradigm shift is not advisable.” – from the NIAID site.Incremental research is safer but needs to be sold as innovation.If reviewers think you're wandering too far outside of the box, your application probably won't score well since the likelihood of success will be perceived as low.New ways of thinking about known problems andtechnological innovations are relatively safe.Paradigm-shifting innovation requires extraordinaryevidence/preliminary data.

29. Preliminary DataPresent data directly relevant to the proposed study.Justify the rationale and feasibility of your specific aims.Include primarily your own data. However, since the page restriction (12 or 6 pages for the narrative) was imposed, many applicants mix key background data with his/her own preliminary data. However, you must present your own data to convince reviewers about technical capability of your lab if you have not published the data.Show your thoughtfulness, rigor and readiness of your lab.Include details (n, error bars, p values, controls, and self-explanatory legends, etc.).Align your preliminary data with specific aims.The more preliminary data, the better.

30. Preliminary DataIf animal data are to justify a clinical study proposal, rigor (statistics, controls, blinded outcome evaluations, selection of outcome directly equivalent to clinical primary outcome measure, all thinkable controls) has a key importance.If human data are to justify a preclinical or clinical proposal, critically assess quality of the preliminary data (e.g., Class I vs. Class IV data) – remember humans are genetically and socially heterogeneous creatures.

31. ApproachIf your specific aim page can pass the reviewers’ critical eyes, this section is the biggest next killing field. The art of study design and setting of clinical studies is fundamentally different from basic science research – heterogeneity of study subjects and biasRandomization – describe how you plan to randomize.Blinding – describe the method of blinding of participant allocation to treatment group (smell and taste of pills, physical interventions, surgical interventions).Unbiased selection of case-subjects and control subjects in case-control studies.Enrollment of the representative sample of the target population.Inclusion and exclusion criteria - include justifications and potential biases. Inclusion criteria: is the study sample non-biased and representative?Exclusion criteria: Are the exclusions justified (sufficient and necessary) and not introducing unnecessary or critical biases?

32. Approach The art of study design and setting of clinical studies is critically different from basic science research –cont’ed.Availability of participants Describe the recruitment strategies, catchment areas, referrals, registry/database, etc. in the context of feasibility and bias.Include a pilot work or similar studies of the population pool.Consider the attrition rate.Data collection/proceduresThorough description of study instruments and their validity and reliability (include a table of instruments and their sensitivity, specificity and reliability statistics).Describe all study measurements and data elements and plans to analyze them.Include training and standardization for reliability assurance.

33. Approach The art of study design and setting of clinical studies is critically different from basic science research –cont’ed.Outcomes Detailed operational definition and specification of each study outcome.Primary and secondary outcome measures with rationale.Blinding evaluators – describe any threats for blinding.How equal surveillance for outcomes will be assured in all study groups.InterventionDetailed description of intervention – standardization, potency, adherence, contamination/co-intervention in the control group.The interventions should not be a “black box.”Data analysis/Sample size calculationsDetailed data management procedures, analytic approach and sample size calculations.Include an intention-to-treat analytic strategy.Handling potential confounders.Handling missing data. Data analysis methods for each outcome with independent variables and covariables to be studied.Use multiple statistical approaches.Your biostatistician is your best friend.

34. Pitfalls and Alternative ApproachIf you do not address them, reviewers will with their “dampened enthusiasm.”Alternative approach does not have to be detailed to the same extent of your methods.

35. BudgetEarly communications with the UF Research Administration and Compliance (RAC) and Institutional Review Board.Start working early on budget for multicenter clinical studies.Know F&A (indirect cost) rate of home and site institutions.Each institution has its own fringe benefit rate.Understand subcontract rules.Upfront subcontract distribution and per-subject reimbursements.The budget may need adjustments due to the sample size adjustments and changes in the number of sites.Making the budget for clinical studies are generally moretime consuming – start early.

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