Clinical Grant Writing:Clinical Grant Writing:Pearls and PitfallsPearls and Pitfalls

James D. Lewis, MD, MSCEJames D. Lewis, MD, MSCE

University of PennsylvaniaUniversity of Pennsylvania

Is the Clinician Researcher a Is the Clinician Researcher a Dying Breed?Dying Breed?

0

5000

10000

15000

20000

25000

30000

35000

1997 1998 1999 2000 2001 2002

MD or MD/PhDApplications

Funded grants

Approx 25% of all grants to MD or MD/PhDApprox 25% of all grants to MD or MD/PhD

Kotchen et al. JAMA 2004;291:836-43Kotchen et al. JAMA 2004;291:836-43

Kotchen, T. A. et al. JAMA 2004;291:836-843.

Percentage of Clinical and Nonclinical R01 Applications, by Priority Score

Human Studies Received Human Studies Received Lower Priority ScoresLower Priority Scores

Review Panel Experience – Review Panel Experience – Little Evidence of BiasLittle Evidence of Bias

220

230

240

250

260

270

280

290

1-25% 26-50% 51-75% >75%

Clinical applications

Nonclinicalapplications

Med

ian

Sco

reM

edia

n S

core

Kotchen, T. A. et al. JAMA 2004;291:836-843.

% Grants Reviewed That Are Clinical

Where Do Clinical Where Do Clinical Applications Go Wrong?Applications Go Wrong?

• AimsAims

• BackgroundBackground

• Preliminary studiesPreliminary studies

• MethodsMethods

• Limitations sectionLimitations section

Abstract & Specific AimsAbstract & Specific Aims

• Only sections that most panel Only sections that most panel members will read (if they even members will read (if they even read these)read these)

• Sell the whole story in a few Sell the whole story in a few paragraphsparagraphs

• State your hypothesis, aims, and State your hypothesis, aims, and designdesign

Specific Aims Need To Be Specific Aims Need To Be SpecificSpecific

• Identify risk factors for exacerbation of Identify risk factors for exacerbation of Crohn’s diseaseCrohn’s disease– VagueVague

• To determine whether consumption of To determine whether consumption of non-aspirin NSAIDs is associated with non-aspirin NSAIDs is associated with exacerbation of Crohn’s diseaseexacerbation of Crohn’s disease– SpecificSpecific

What Does This Have To Do What Does This Have To Do With Grant Writing?With Grant Writing?

A Hypothesis Is EssentialA Hypothesis Is Essential

• P01, R01, K08, K23, K01P01, R01, K08, K23, K01– Hypothesis testing is essentialHypothesis testing is essential

• R03R03– Hypothesis testing preferredHypothesis testing preferred– Also fundableAlso fundable

• Proof of principleProof of principle• FeasibilityFeasibility• Hypothesis generation?Hypothesis generation?

Aims Must Be AchievableAims Must Be Achievable

Background SectionBackground Section

Background SectionBackground Section• Tell a story - Not a review articleTell a story - Not a review article• Refer to your prior work if appropriateRefer to your prior work if appropriate• Selected referencesSelected references

– Demonstrate your knowledge of the fieldDemonstrate your knowledge of the field– Reviewers’ articles?Reviewers’ articles?

• Conclusion of background section – Conclusion of background section – Need for your proposed study is Need for your proposed study is obvious!!! obvious!!!

Preliminary StudiesPreliminary Studies

• Support for your hypothesisSupport for your hypothesis– Present Present youryour background research that led background research that led

to current hypothesisto current hypothesis

• FeasibilityFeasibility– Required data availableRequired data available– Study population availableStudy population available– Measurement tools accurate / responsiveMeasurement tools accurate / responsive– You and your team’s qualificationsYou and your team’s qualifications

Sell YourselfSell Yourself

• Dr. Smith is an Assistant Professor of Dr. Smith is an Assistant Professor of Medicine at XYZ University. She has a Medicine at XYZ University. She has a master’s degree in Clinical Epidemiology from master’s degree in Clinical Epidemiology from ABC Univ. She has more than X years ABC Univ. She has more than X years experience in caring for patients with IBD and experience in caring for patients with IBD and conducting research in the field. Her previous conducting research in the field. Her previous research experience includes … (refs). Of research experience includes … (refs). Of particular relevance to this application, she …particular relevance to this application, she …

Methods SectionMethods Section

Form = FunctionForm = Function

Methods SectionMethods Section

• Details essentialDetails essential

• Address each aimAddress each aim– Inclusion / Exclusion criteriaInclusion / Exclusion criteria– Data collectionData collection– AnalysesAnalyses– Potential limitationsPotential limitations

Inclusion / Exclusion CriteriaInclusion / Exclusion Criteria

• Appropriate to achieve aimAppropriate to achieve aim– Will answer questionWill answer question– ObtainableObtainable

• ““Reagent grade patients” Reagent grade patients” – Stephen Targan circa 2000Stephen Targan circa 2000

• Internal validity usually more Internal validity usually more important than generalizabilityimportant than generalizability

Data CollectionData Collection

• How will every item be measured?How will every item be measured?

• Primary data collectionPrimary data collection– InstrumentsInstruments– Assays (biochemical, endoscopy, etc)Assays (biochemical, endoscopy, etc)

• Secondary data analysisSecondary data analysis– Limited by quality of existing dataLimited by quality of existing data– Must justify accuracy of dataMust justify accuracy of data

Statistical IssuesStatistical Issues

• Every aim needs a separate analysis Every aim needs a separate analysis planplan

• Define outcome and exposure variablesDefine outcome and exposure variables– How will the variable be categorized? How will the variable be categorized?

(continuous, dichotomous, quintiles, etc.)(continuous, dichotomous, quintiles, etc.)

• Rationale for statistical planRationale for statistical plan– Get biostatistical help!!!!Get biostatistical help!!!!

Sample Size – Don’t Make a Sample Size – Don’t Make a Rookie MistakeRookie Mistake

Sample SizeSample Size

• Easy target for the reviewerEasy target for the reviewer

• Always based on assumptionsAlways based on assumptions

• Provide data or references to Provide data or references to justify your assumptionsjustify your assumptions

Logistics: Who, When, & HowLogistics: Who, When, & How

• Sample/CRF transportationSample/CRF transportation

• Data entryData entry

• MonitoringMonitoring

• Data cleaning and analysisData cleaning and analysis

• TimelineTimeline

Human Subjects ConcernsHuman Subjects Concerns

• Is your study ethical?Is your study ethical?

• Appropriate safety measures?Appropriate safety measures?

• Women, children and minorities?Women, children and minorities?

• Funding R01 human subject proposalsFunding R01 human subject proposals– No human subject concerns – 24.9%No human subject concerns – 24.9%– Human subject concerns – 12.5%Human subject concerns – 12.5%

Kotchen, T. A. et al. JAMA 2004;291:836-843.

No Clinical Study Is PerfectNo Clinical Study Is Perfect

LimitationsLimitations• Identify your limitationsIdentify your limitations

– The reviewers will see them anywayThe reviewers will see them anyway

• Explain why they will not compromise Explain why they will not compromise your results and interpretationyour results and interpretation– Not a real problemNot a real problem– Your design will prevent the problemYour design will prevent the problem

• If you don’t explain it, the reviewer If you don’t explain it, the reviewer won’t see why it is not a problemwon’t see why it is not a problem

ExampleExample• The CDAI is an imperfect measure of disease activity, The CDAI is an imperfect measure of disease activity,

albeit with sensitivity and specificity for active CD both albeit with sensitivity and specificity for active CD both greater than 90%. Any misclassification resulting from use greater than 90%. Any misclassification resulting from use of the CDAI should be nondifferential. As such, any bias of the CDAI should be nondifferential. As such, any bias should be toward the null hypothesis. Because of the should be toward the null hypothesis. Because of the small degree of misclassification with the CDAI, the small small degree of misclassification with the CDAI, the small amount of bias resulting from use of the CDAI would not amount of bias resulting from use of the CDAI would not be expected to obscure a clinically important affect of be expected to obscure a clinically important affect of NSAIDs on disease activity. In addition, we have NSAIDs on disease activity. In addition, we have increased our sample size by 15% to account for the increased our sample size by 15% to account for the possibility of non-differential misclassificaiton bias possibility of non-differential misclassificaiton bias resulting from use of the CDAI.resulting from use of the CDAI.

DetailsDetails• Every sentence countsEvery sentence counts

• Defend every statementDefend every statement–Empiric data - bestEmpiric data - best

–References – good alternativeReferences – good alternative

–Rationale – better than nothingRationale – better than nothing

Non-Science MistakesNon-Science Mistakes

• Formatting rulesFormatting rules

• Budget rulesBudget rules

• Time frameTime frame

• Spelling and grammar mistakesSpelling and grammar mistakes

• Table and figure numbersTable and figure numbers

• Missing expertise - Missing expertise - biostatisticianbiostatistician

• Letters of supportLetters of support

Non-Science MistakesNon-Science Mistakes

• Run out of energy for final aimRun out of energy for final aim

CohortC-CRCTITTSS

Plan AheadPlan Ahead

• 6 to 12 months to prepare a submission6 to 12 months to prepare a submission

• Get feedback from investigators at your Get feedback from investigators at your institutioninstitution– Minimum of 2 weeks before deadlineMinimum of 2 weeks before deadline

• Assume the deadline is 48 hours earlyAssume the deadline is 48 hours early

• Last day for final proof reading and Last day for final proof reading and collatingcollating

If At First You Don’t If At First You Don’t Succeed…Succeed…

• Find out whyFind out why

• Reviewers critiques are the roadmap to Reviewers critiques are the roadmap to revising your proposalrevising your proposal

• Need to address every critique in a Need to address every critique in a resubmissionresubmission

• Make it easy for the reviewers to see Make it easy for the reviewers to see how you respondedhow you responded

If At First You Don’t If At First You Don’t Succeed…Succeed…

• Try, try againTry, try again• Anticipate at least one resubmission to Anticipate at least one resubmission to

achieve a fundable scoreachieve a fundable score• 1998 – 1999 Only 37% of those eligible 1998 – 1999 Only 37% of those eligible

to submit revised applications did soto submit revised applications did so• While historically 30% of grants are While historically 30% of grants are

funded in a given cycle, more than 40 to funded in a given cycle, more than 40 to 45% of grants are ultimately funded45% of grants are ultimately funded

Kotchen, T. A. et al. JAMA 2004;291:836-843.

Good Grants Produce Good Grants Produce Good ScienceGood Science

Resources on the WebResources on the Web

• http://grants1.nih.gov/grants/http://grants1.nih.gov/grants/new_investigators/index.htmnew_investigators/index.htm

• http://grants1.nih.gov/training/http://grants1.nih.gov/training/careerdevelopmentawards.htmcareerdevelopmentawards.htm

• http://grants1.nih.gov/grants/forms.htmhttp://grants1.nih.gov/grants/forms.htm