CAS NIH R-Grant Workshop

Dr Lindsey N. Shaw

Part 1: Introducing the Task and My Experience

Help with NIH Funding – a Difficult Task!

I Have Some Grant Writing Experience

My Best Insight – Study Section Experience

But I don’t have all the answers!

MRSA – the Ultimate Super Bug!

Global Infectious Disease

S. aureus – the Leading Western Pathogen

Meningitis/Brain Abscesses

EndocarditisPneumonia (necrotizing)

Osteomyelitis

Septic arthritis

Food Poisoning

Toxic Shock Syndrome

2010

Penicillin

Methicillin

Vancomycin

1950 1970 1980 1990

Penicillin

Methicillin

1960

Ciprofloxacin

Ciprofloxacin

1940 2000

Dru

g In

trod

uced

Firs

t Cas

e of

Res

ista

nce

Rifampicin

DaptomycinLinezolid

Rifampicin

Daptomycin

Linezolid

Tigecycline

Vancomycin

Drug resistance timeline

Gentamicin

Gentamicin

Cefalotin

Cefalotin

Tetracycline

Tetracycline

• StaphVAX (Nabi)– Targets Capsule CP5 and CP8

• AltaStaph (Nabi)– Targets Capsule CP5 and CP8

• NeuTec Pharma– Unreported Surface Antigen

• Veronate (Inhibitex)– Targets ClfA (Surface Antigen)

• Vaccine Research Int– Can/Clf/FnBp/Eap (Surface Antigens)

• ETI-211b (Elusys)– Spa (Surface Antigen)

• SRP(Sanofi Pasteur)– Siderophore/Antiporter

• Novartis– IsdB/SdrD/SdrE/IsdA (Surface Antigens)

• Merck– IsdB (Surface Antigen)

• Aurexis (Inhibitex)– Targets ClfA (Surface Antigen)

• Biosynexsus– Wall Techoic Acid

FAILED Phase III (2002)

FAILED Phase II (2006)

Dormant Since 2009

FAILED Phase III (2007)

FAILED Phase II (2011)

Surely vaccines will work?

FAILED Phase II/III (2011)

FAILED Phase II (2006)

Dormant Since 2009

Dormant Since 2007

Dormant Since 2007

FAILED Phase III (2011)

Post-Antibiotic Era

What Does this Add Up To?

SIGNIFICANCE

Part 2: Where to Begin – the Groundwork

What I Cannot Do For You!

Learning on the Job

What I Can Do For You!

The NIH’s 21 Institutes

Their Remit

Their Budgets

The Paylines

Their Success Rates

Their Due Dates

R01 =

R03/R21 =

R15 =

Timing and FY Budgets

Picking a Study Section

Creating a Funding Strategy

Diversification

Exploit Serendipity

Maximizing Return on Investment

R01 R21

But Remember, Quality, Not Just Quantity

Scoping out the Competition

Other Groundwork - Networking

Elevator Pitch

Part 3: Getting Started – the Types of Applications

RFA vs Investigator Initiated

RFA vs Investigator Initiated

Type of Application

Grant Amount Years Scope Renewable ESI

R01 $1,250,000+ 4-5 Discrete, specified, circumscribed project

Yes Y

R21 $275,000 2 Exploratory, high risk, high reward No N

R03 $100,000 2 Small project, pilot or feasibility studies

No N

R15 $300,000 3 Support meritorious research, Expose students to research, Strengthen the research environment of the institution

Yes N

R15s the Basics

Institution cannot receive >$6M a year from NIH(USF Med school ineligible, main campus is)

12+1 Pages, due 25th of the month

Supports Meritorious Research

Student Involvement is paramount

Must strengthen the research environment

Preliminary Data not Required!

Renewable

Extra Considerations

Mechanism Specifics

R15 Issues

R15 Positives at USF

R03s the Basics

Preliminary Data Not Required!

6+1 Page Application (same size as R21)

16th of the month due date (same as R21)

Success rates a little better (22.5% > 21.6%)

Comes down to risk and project scope

Extra Considerations

Cost Benefit Analysis

Career Stage Considerations

Might consider starting small to

be good

But, without a track record, can you get the work

done in time?

R03s rarely lead to R01s

R21s the Basics

Preliminary Data Not Required!

6+1 Page Application

16th of the month due date

$175,00 more than R03

Need to deliver

For projects that need a shot in the arm

Extra Considerations

High Risk, High Reward

Exploratory – think about language

Two or Three Aims?

Conservatism

R01 R21

Fishing Expedition

R01s the Basics

Preliminary Data Definitely Required!

12+1 Page Application

5th of the month due date

Up to $1,250,000 over 5 years

Not easy to get!

Extra Considerations

New is Good for R01s

ESI: Early Stage Investigator<10 years since terminal degreeNever been PI of an R01

NI: New Investigator>10 years since terminal degreeNever been PI of an R01

ESI/NI Help

Other R01 Benefits

R56

Selective Pay NominationDecided by POsFunds a small number of grants that miss the

payline, but are programmatically important

Part 4: Logistics & Review Criteria

Work to a Timeline

Just because you CAN write a grant in 2 weeks, doesn’t mean you should!

Self EvaluationProven track record – particularly for R01sProductivityTrainingNew field – smaller grant? Do you have papers?

Got an Idea?Gap in the KnowledgeCompetition – enough space?ImpactFollow serendipity

Crafting Your Aims – Gut Check

Ask yourself these questions:

Would my reviewers see my aims as tackling an important problem in a significant field?

Would they would view my aims as being innovative?

Do my specific aims test my hypothesis?

Are they doable within the period I am requesting?

Are the aims and hypothesis concrete and focused?

Can I define endpoints my reviewers will be able to assess?

Crafting Your Aims – Check Point

IMPACT

Significance

Investigator

Innovation

Approach

Environment

Human Subjects, Animals, Biohazards

Resubmission/Renewal

Review Criteria

Significance

Understanding Significance

Significance

Make sure all your reviewers—not just your assigned reviewers—grasp the importance of your project

Throughout, focus on the significance of your research to your field and to public health

Convince your reviewers how the niche you've selected can push forward the frontier of knowledge in your field.

Highlight the significance in your Abstract and Specific Aims — the sections all reviewers will read

Explicitly state:

How your research will advance your field

How it will fill knowledge gaps, and how it relates to research underway

How the work is new and unique

How it meets the NIH mission to:

Improve health through science, by leading to cures, treatments, or preventions for human disease

How convincing you are will profoundly affect your score

Significance

Significance

If most of your reviewers are fluent in your field, don't spend much effort convincing them of the significance of your project

Reviewers think of most work in their field as significant

They will be particularly energized by an application that addresses critical research and has a promising strategies

Reviewers make judgments based on their experience and expertise.

Scoping your reviewers out and writing to their perspective is key

Convince them of the significance of your research based on the composition of your study section.

Scenario 1 – Study section is narrowly focused in your field (reviewers are fluent in your area): spend much less effort convincing them of your project's significance.

Scenario 2 - Study section is more diverse: write more on significance

Significance 101

In the Significance section, you describe the importance of your hypothesis to the field (especially if your reviewers are not in it) and human disease.

You point out significance throughout the application.

The application shows that you are aware of opportunities, gaps, roadblocks, and research already underway

You state how your research will advance the field

Based on the roster, can you assume your reviewers will see things the way you do?

Significance Checkpoint

Let other people fill in gaps in your expertise

Choosing highly experienced people to be on your team will help build trust in the future success of your project.

Expand your pool of expertise by recruiting consultants and collaborators, especially those who are known and respected

Get commitments from collaborators at the planning stage - don't waste time planning work you cannot deliver.

Use the credit card.

Senior-level collaborators will typically work part-time for credit (e.g., the potential of future publications), rather than pay.

Investigator

Collaborations are common, but there are drawbacks.

No control over the execution of that part of the research

Working out the order of authors on future publications.

Collaborators may want to use data generated for their grants and may see themselves as the lead.

Collaborators play an active role in the research. The grant may pay part of their salary via a subaward

Consultants provide advice or services that fill gaps, e.g. supplying reagent/software. They usually receive a fee rather than salary

Investigator

Here are some questions to consider:

Is the collaborator at your institution?

If not, what inter-institutional agreements may be necessary?

You might want to look at multiple PI agreements as an example.

What intellectual property arrangements do you need to make?

Investigator

Innovation

Understanding Innovation

Be Innovative, But Be WaryInnovation is a review criterion – so think outside the box — just not too far!Innovation is the knowledge, tools, resources your project can contribute to the field.It's enough to show how the work you propose is new and unique and will push the frontiers of knowledge aheadFor most people, the goal is significant incremental progress, not a giant leap forward. This generally means improving on or proposing a new application of an existing concept, method, or clinical intervention.

Innovation

If you are a new investigator or are entering a new area, expect reviewers to be skeptical if your research is highly innovative.

Note that if your reviewers feel they could not get the work done, they are unlikely to think you could either.

Reviewers may also take a challenge to the status quo as a challenge to his or her world view or research.

Novel methodology – that you can actually do – is always a huge help

Innovation

After finishing the draft innovation section, check that:

You show how your research is new and unique

Explores new scientific avenues

Has a novel hypothesis

Will create new knowledge.

If you are a new investigator:

Do you explain how your project can refine, improve, or propose a new application to an existing concept/method?

Innovation Checkpoint

If you go for the other option described in NIH's definition: show how your research can shift a current paradigm, do you:

Make a very strong case for challenging the existing paradigm?

Have data to support the innovative approach?

Have strong evidence that you can do the work?

Innovation Checkpoint

Sketch Out Experiments for Your Research Strategy

If your Specific Aims section is the big-picture part of your application's Research Plan, the Research Strategy is its nuts and bolts.

In your Research Strategy show your reviewers that you can not only "talk the talk" but also "walk the walk.“

Start planning by sketching out experiments you could do to conclusively accomplish each aim, including alternative pathways you could pursue.

Having references for techniques avoids a lot of problems

Approach

Plan what you would do if:You get an exciting new lead.You get a negative result.

Map out alternative experiments too, making sure they track with your planned aims.Showing alternatives will help convince reviewers you are well-prepared to deal with unknowns and reveal how you thoughtfully planned your research. You may want to create a flowchart and timeline for planning and possibly include it in the application.Approach is the most common place for things to go wrong

Approach

After finishing a draft Approach section, check that:

You include enough background and preliminary data to give reviewers the context and significance of your plans.

Each of your Specific Aims results in a set of experiments:

That can test the hypothesis

Show alternative experiments and approaches in case you get negative or surprising results.

Your experiments can yield meaningful data to test your hypothesis.

Approach Checkpoint

As a new investigator, include enough detail to convince reviewers you understand and can handle a method.Is it clear what you do well and what unique skills you and your team bring to the research? If you think reviewers may have doubts, explicitly state

your team's resources and expertise.Do you describe results and anticipated their implications.Do you keep track of, and explain, who will do what, what they will do, when and where they will do it, how long it will take, and how much money it will cost.Does your timeline show when you expect to complete your aims?

Approach Checkpoint

Environment

Environment is Easy – Get it Right!

Top 10 Reasons for Application Failure

1. Poorly formatted, typographical errors, grammatical errors, lack of proofreading, or unappealing presentation.

2. Insufficient preliminary data, or preliminary data do not support project's feasibility.

3. Overly ambitious Specific Aims or Research Strategy.

4. Unimportant question; lack of significance to the field or public health.

5. Lack of investigator expertise or collaborators on the team.

6. Lack of innovation or new ideas.

7. Lack of a strong, original hypothesis and Specific Aims.

8. Failure to identify potential pitfalls and lack of alternative approaches.

9. Failure to demonstrate knowledge of the field (didn’t cite relevant papers or account for alternative viewpoints).

10. Failure to request a study section or get advice on study section choice (so the application ended up in the wrong study section).

Top 10 Reasons for Application Failure

Part 5: Other Assembled Advice

Ask: Can the research make a difference?Will it open up a new area of discovery ?Will it develop a new approach to a major problem?

Get outside opinionsDon't assume others will see you work as you do

When considering projects, get advice from experts, including colleagues and NIH program officers

Make sure your strengths match up with potential projects, and you are within your area of expertise

You Can’t Do Science in a Vacuum

Create Specific Aims that fit the mechanism

Make sure they have clear endpoints reviewers can readily assess

Create a hypothesis (or hypotheses) that is well focused and testable by the aims and experiments

Make sure your project is not getting too big

Limit scope. Avoid being too ambitious. Create a project of limited scope that is doable within the time and resources appropriate for you to request, especially if you are a new investigator.

Size, Scope and Overly Ambitious

See whether you have all the necessary resources and expertise to perform the experiments

Think about hiring – who and how many?

Make sure your team has first-hand experience with the science and methods

If the team is multidisciplinary, make sure NIH has a review committee that will be able to effectively review the application

Check that you have access to necessary equipment, especially large equipment

Resources and Experience

Rate the project and decide whether to pursue it. Ask NIH program officers whether your idea would fit their institute – what do they think?Ask experts in your institution and other colleagues to rate your ideaGive a presentation on the project and possible research approachesBased on this input, rate the impact of your topic on a scale from 1 (highest) to 9 (lowest), the NIH review scaleTake another look at your NIH peer review committee. What will they think of your idea?

Self Triage

Design a project that is a bit outside of the box—but not too much!Think of innovation as what your project will contribute to your field if it succeedsIf you are a new investigator, strive for significant incremental progress, not a giant leap forward.It's enough to show how the work you propose is new and unique and will add significantly to existing knowledge.Know the policy areas that make your application more complex.IRB, IACUC, rDNA

Be Novel – Just Not Too Novel!

Write To Your Audience

Fire up your reviewers by convincing them of these key points.

1. Your proposal has a strong potential to have a high impact on its field of science.

2. Your approach is logical and innovative.

3. Your institution will give you the support you need.

4. You (with the help of your collaborators) are the person to do the research.

5. Testing your hypothesis is worth NIH's money.

1. Can your research move your field forward?

2. Is the field important—will progress make a difference to human health?

3. Can you and your team carry out the work?

Three Big Questions

As you write your application, check that:You understand who your audience is so you know what they're looking for.Realize that although only a few reviewers read your full application, the entire study section will score it.Spell out why you should be funded by describing how your project is high impact.Make it easy for assigned reviewers to grasp the goals, significance, and feasibility of the project.Your Abstract, Specific Aims, and Significance can be understood by your assigned reviewers and the rest of the study section

Checkpoint

Methods unsuited to the objective.Lack of focus in hypothesis, Specific Aims, or Research Plan.Study not likely to produce useful information.Problem more complex than investigator appears to realize.Proposed project is a fishing expedition lacking solid scientific basis, i.e., no basic scientific question being addressed.Insufficient statistical expertise either to design the project or conduct the research.Proposed model system not appropriate to address the proposed questions.Relevant controls not included.Contradictory data were obtained by the investigator and that reported by others.

Design Issues

Rationale for experiments not provided, i.e., why they are important or how they are relevant to the hypothesis.

Too little detail in the Research Plan to convince reviewers the investigator knows what he or she is doing.

Direction or sense of priority not clearly defined, i.e., experiments do not follow one another and lack a clear starting or finishing point.

Not clear which data were obtained by the investigator and which were reported by others.

Writing and Presentation Issues

Reviewers May Not "Get It"Peer reviewers are knowledgeable, experienced scientists, but they don't know everything. Make your application as clear as possible so they can understand your idea.Problem: They may not be familiar with all your methods.Solution: Write to the nonexpert in the field.

Problem: They may not be familiar with your lab.Solution: Convince them you can do the job.

Problem: They may get worn out from reading many applicationsSolution: Write clearly and concisely, and make sure your

application is neat, well organized, and visually appealing.

Problems and Solutions

You have just a few seconds to make a great first impression.

At first glance, reviewers know whether they eagerly anticipate or dread reading your application.

All the more reason it should be neat, well organized, and easy-to-read.

Keep in mind that your reviewers have a multitude of applications to evaluate, so they'll appreciate one that's visually appealing and super user friendly.

Presentation, Presentation, Presentation

Divide into sections. Use headers to create structure and white space. Also, try breaking up text since blocks of uninterrupted text are depressing to look at. Guide with graphics. Graphics, timelines, and other visuals help reviewers grasp a lot of information. Label all materials clearly. Make it easy for reviewers to find information.Edit and proofread. Your presentation—writing and appearance—can make or break your application, so eliminate typos and internal inconsistencies. And, since two or more sets of eyes are better than one, ask other people—including nonscientists—to read your application.

Presentation, Presentation, Presentation

Savvy PIs create opportunities to drive their main points home.

They don't stop at the Significance section to emphasize their project's importance, they look beyond their biosketches to highlight their team's expertise.

Don't take a chance your reviewer will gloss over that one critical sentence buried somewhere in your Research Strategy

Write yourself an insurance policy against human fallibility: if it's a key point, repeat it, then repeat it again.

Packaging

Add more emphasis by putting the text in bold, or bold italics (in the modern age, we skip underlining—it's for typewriters).While describing a method in the Approach section, state your collaborators' experience with it.Point out that you have access to a necessary piece of equipment.When explaining your field and the status of current research, weave in your own work and preliminary data.Delve into the biology of an area to make sure reviewers will grasp the importance of the research, and understand the field and how your work fits into it.

Packaging

In the top-notch applications we reviewed, organization ruled but

followed few rules. While you want to be organized, how you go

about it is up to you.

Final Piece of Advice

Part 6: Review – the Study Section

http://www.youtube.com/watch?feature=player_embedded&v=fBDxI6l4dOA#at=558

CSR Video of Study Section