bettie m. steinberg, phd chief scientific officer the feinstein institute for medical research
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Bettie M. Steinberg, PhDChief Scientific Officer
The Feinstein Institute for Medical ResearchDean, Elmezzi Graduate School of Molecular MedicineProfessor and Chair, Department of Molecular Medicine
Hofstra North Shore-LIJ School of Medicine
“Designing and Preparing a Grant Application for Clinical Studies;
Initial Results of a Funded Study"
Disclosure Statement
• The Presenter, Dr. Bettie Steinberg, has the following conflict:
Receives a grant from Pfizer, Inc. for celecoxib and matched placebo for clinical trial
Learning Objectives
• Hypothesis – Definition – Types
• Using the medical literature – identifying a clear, structured, searchable clinical
question to be addressed
• Applying research to clinical care/grantsmanship– Planning and presenting assessment of study design,
performance & analysis
Choosing Your Project:Long-term and Short-term views
• Long term– Pick area where you wish to become the expert
• Based on clinical interest or research you have already done
• Chose topic with high impact• Select area with gaps no one is filling
– Create 10 year plan for research goals – Divide into 3-4 sections
• Short term– Actual study will address first section of plan– Identify immediate pressing problem – important and
unique– Write one sentence on project, impact and hypothesis
Hypothesis• Two types of studies:
– Hypothesis Testing: study tests idea to see if probably correct
– Hypothesis Generating: study collects data, look for patterns that might generate a hypothesis
• Hypothesis: Explanation or “educated guess” that is proposed in order to explain certain events or observations, to provide guidance for further investigation
– A hypothesis must be capable of being tested
• Two types– Null hypothesis: treatment will not differ from control– Alternative hypothesis: treatment will be effective
Generating a Hypothesis
• Can be based on your own observations
• Can be based on reading literature
• Or (usually is) combination of both
Your expertise – pediatric nephrology
• Epidemiology studies show that high sodium diets correlate with elevated blood pressure in adults, although the efficacy of sodium restriction for hypertension is not clear cut.
• Can you create a hypothesis to test in a study of kids?
When You Have Your Hypothesis• Define exactly what you propose to do• Think of all problems/complications you can
– There will be plenty you did not think of
• Get statistical help early – especially when a clinical study
• Identify funds to do study– Best source outside grant
• Write grant application, get funds• Conduct study• Analyze data• Write paper(s)• Write next grant
Writing A Good Grant Is Not Magic
The Grant – Based on A Good Idea
• The IDEA must be: Novel/Original/Creative/Significant
– Want a leap of concept, not just obvious next step
– Reviewer should think “I wish I had thought of that!”
– Potential results should move field forward
What You Need to Write a Successful Grant
• Communication skills– Must write clearly, simply, organized
– Tell a story
– “Good writing cannot make a good grant out of a bad idea, but bad writing will make a bad grant out of a good idea” – no spelling or grammar errors!
– Get help if writing is not your strength
• Persistence, persistence, and more persistence
Four Basic Elements To Writing The Grant
• What you want to study? – What is the question or problem to be studied?
• What need do you plan to fill?– Why does it matter?
• Why you should get the money – Not somebody else
• How you’re going to do it – Approach, study design
“Over-ambitious” is Common Major Error
Don’t propose more than is reasonable to do in time allotted
Very rare for grant to be criticized because it does not propose enough – common to be criticized as over-ambitious or unfocused, even if it includes exciting ideas
You As the Investigator
• Can study be done? by you? here?
– Have you or someone else published methods or preliminary data?
– Do you have the facilities, patients, etc.?
– Include collaborators for strength
• don’t try to be an expert at everything
Scientific Parts Of Most Grants• Description (abstract) – must fit in allotted space on form• Specific Aims• Research Strategy
– Significance, Innovation, and Approach• Resources/facilities – no limit, but normally 1-2 pages
– Descriptive
• Appropriate safeguards – human subjects, animal welfare
• Consortium/contractual arrangements, letters of support, etc.
• References• Appendix (if permitted)
– questionnaires, informed consent forms, etc.
NIH Review Criteria -Write All Grants to Address These Points
• Significance: Important problem? How will scientific knowledge or clinical practice be improved?
• Innovation: Novel concepts, approaches, methods?– Challenge or shift research or practice paradigms?
• Approach: Strategy, methodology and analyses appropriate for study? Potential problems presented and managed? Protection of human subjects, inclusion of children and minority plans OK?
• Investigators: Well suited? Sufficient experience and training? Collaborators?
• Environment: Will it enhance likelihood of success?
Ways to Kill A Grant
• Major ethical or design problem
• Central scientific question not important
• Ideas not original, important or exciting
• PI and/or research team lacks the experience or ability to carry out proposed work
• Preliminary data weak or absent – no justification for the hypothesis
• Proverbial house of cards
• Scope too ambitious, or with multiple hypotheses
• Don’t follow instructions
• Write over weekend
Description (Abstract)
• Summary of the whole grant– Only part that is public knowledge on NIH Grants
• Critical First Page– First thing reviewer reads
• I leave to the end, after the whole grant is finished• If do first, and then change grant, must rewrite
Structure of Specific Aims Page• Narrative Paragraph
– Define problem and significance– State long and short term goals, how address problem– Summarize expected outcome(s) – State hypothesis (can put in bold or italic to emphasize)
• Specific Aims– Each should test part of hypothesis – otherwise why do– Each should be linked but independent of other aims –
don’t set up house of cards– Aims should address mechanism, not correlations
• Keep grant narrow, keep it focused and keep the number of aims small (3-4 aims for 4-5 years work)
Research StrategySignificance and Innovation
• This is where you set up the rationale and novelty for your proposal
• Explain importance of problem or critical barrier to progress that you will address
• Describe how concepts, methods, technologies or treatments in field will be changed if proposed aims are achieved– Need a conceptual leap, not just a “better mousetrap”
• Explain how project will improve scientific knowledge, technical capability, and/or clinical practice– Review of current literature is part of this
• –All this in about 1-2 pages for most grants
Preliminary Data• Do you need?
• Very helpful, even for exploratory and small grants– Supports your idea
– Proves you (your mentor/collaborator) can do what you propose
– Amount of preliminary results depends on grant type
• Preliminary data must be very high (publication) quality - don’t include poor quality data– “There are no preliminary results, just unpublished
ones”
• Organize so reviewer can see your points
Sample Preliminary Data
“We first asked whether COX-2 was expressed in papilloma tissues” (gives flow and thought process)
COX-2
Negative control
Normal PapillomaA
A: Paraffin embedded tissues were incubated with anti-COX-2 (Santa Cruz) or PBS (control), briefly counterstained with hematoxylin and detected using DAB stain. B: Extracts from normal and papilloma tissues were analyzed by western blot. Membranes were reprobed for β-actin to confirm equal loading and transfer, and intensity determined by densitometry. Graph shows data from 6 papillomas and 7 normal tissues. * p=<0.01 by Student t-test. COX-1 levels were extremely low, and comparable in both types of tissue (not shown).
Rel
ativ
e C
OX-
2 le
velsB.
0123456
Normal
Papilloma
*
0123456
0123456
Normal
Papilloma
*
Research Strategy
• Describe overall strategy, methodology, and analyses to accomplish specific aims
• Discuss potential problems, alternative strategies, and benchmarks for success
• If in the early stages of development, describe any strategy to establish feasibility
– Address management of any high risk aspects
• Point out anything that may be hazardous and precautions to be taken
Overall Strategy, Methodology, Analyses Clinical Study
• Several essential sections – I put in a small table of contents for this section
– Research question pg __– Study Design/Approach pg __– Patient Sample pg __– Attrition pg __– Detailed Treatment Plan (for efficacy studies) pg __– Data Management pg __– Time Periods for Study pg __– Biostatistical Considerations pg __– Sample Size Determination pg __
• Include Case Report Forms (CRFs), Consent form, Data Safety Monitoring Plan (DSMP), etc. in appendix
•Research Question – one short paragraph, clearly stated
•Study Design – use a diagram! If you cannot draw one, you have a problem
Overall Strategy
CelebrexCelebrexPlacebo
PlaceboPre Treat
-6 -3 0 3 6 9 12 15 18 21 24
Months on Study Drug
Arm 1
Arm 2
(Endoscopy, biopsies, blood sample collection at each 3-month time point)
Overall Strategy, con.• Patient sample
– inclusion, exclusion criteria; how recruit; enrollment procedure
– accrual plan – what if problem?• Attrition - must address, predict rate• Detailed treatment plan
– narrative - who will do what, when– maybe a table with all lab tests, evaluations, etc
• Time periods for study– figure showing first enrollment and last, interim data
analysis, etc• Biostatistical analyses – work with an expert• Sample size calculations – critical for feasibility
Clinical ProtocolProcedure -6
mo-3 mo
-4 wk
-7 day
0 3 mo 6 mo
9 mo 12 mo
history/physical*
A A A A A A A
chest x-ray A
CBC/diff.* A A A A A A A
liver function / creatine tests.*
A A A A A A A
s- Beta HCG** F F F F F F
randomize A
start drug X Y
directendoscopy
A A A A A A A
biopsies and blood
A A A A A A A
Finally, The Abstract Page
• Take key sentence(s) on significance of problem from Significance section
• Summarize in 1-2 sentences the essential background
• State or paraphrase the hypothesis or goal
• State the Specific Aims and the general approach you plan to use
• Must fit in space defined
Respiratory Papillomas –Caused by HPVs 6 and 11
Tracheal disease
Pulmonary disease
Moderate disease Severe diseaseMild disease
Respiratory Papillomas Express COX-2
COX-2
Negative control
Normal PapillomaA
Rel
ativ
e C
OX
-2
leve
ls
B.
0
1
2
3
4
5
6Normal
Papilloma
*
0
1
2
3
4
5
6
0
1
2
3
4
5
6Normal
Papilloma
*
Cyclooxygenase -2 (COX-2)Arachidonic Acid
PGG2
PGH2
PGD2 PGE2 PGF2a PGI2 TXA2
COX-2
COX-2
Inducible synthases
• Elevated in many premalignant and malignant tumors• If express in transgenic mouse skin, get tumors• Stimulates EGF Receptor• Stimulates tumor angiogenesis – induces VEGF• Inhibits apoptosis• Suppresses TH1 immune response
Inhibiting COX-2 Reduces Papilloma Cell Proliferation and Increases Apoptosis
R
elat
ive
Pro
lifer
atio
n
Celecoxib (µM)
*
0 2.5 5.0 7.5
*
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Normal
Papilloma
Rel
ativ
e A
pop
tosi
s
*
*
* *
*
0 2.5 5 7.5
Celecoxib (µM)
*
* *
*
0
1
2
3
4
5
6
* p < 0.05** p < 0.01
COX-2 and PGE2 Regulate Expression of HPV In Vitro
0
0.5
1
1.5
2
2.5 *
*
**
HPV11 HPV16
control
PGE2
celecoxib
R
elat
ive
E6/
E7
mR
NA
-6 -3 0 3 6 9 12 15 18 21 24
Months on Study Drug
Arm 1
Arm 2
Scheduled surg.
12 months 18 months
Trachea, Subject 3
Months after randomization
0
0.02
0.04
0.06
0.08
0.1
0 3 9 12 15 18 21 24 30 41 69
G
row
th R
ate Subject 3
0
0.02
0.04
0.06
0.08
0.1
0 3 6 9 12 15 18 21 24 36 50 55 60
Months after randomization
G
row
th R
ate Subject 1
0
0.02
0.04
0.06
0.08
0.1
0 3 6 9 12 15 18 21 24 34 60 72
Months after randomization
G
row
th R
ate-
Subject 2
Celebrex
CelebrexPlacebo
Placebo Pre Treat
Clinical Celecoxib Study Design
Preliminary Results
Laryngeal Response – 28 patients Tracheal Response
Preliminary Results Summary• Enrolled to date: 50 subjects
• Patients with >6 months follow-up after randomization: 29
• 13 with clinical response – reduction in severity >50%
• 9 free of disease for > 6 months
– 5 free of disease for a year or more
• 4 free of disease for > 3 months, but not disease-free at two successive surgeries
– marked reduction in disease severity
• 16 with no significant remission of laryngeal disease
– One patient with persistent laryngeal disease now free of tracheal disease
Current Questions – In Progress• Is celecoxib an effective adjunct treatment for RRP?• Is improvement maintained when celecoxib therapy
stops?
• Do clinical characteristics (juvenile vs. adult onset, gender or HPV type) correlate with response?
• Are molecular markers consistent with a COX-2 dependent mechanism of response?
• Does celecoxib treatment reduce the prevalence of latent HPV DNA?
• How does COX-2/PGE2 impact on local immune response to HPV?
• Does COX-2/PGE2 also play a role in HPV+ tonsil cancers?
Thank You
Clinicians
Allan AbramsonMark ShikowitzGinny Mullooly
Physicians at participating sites
Laboratory Studies
Alexandra LucsRong WuRay PicaAli Afzal
All Participating RRP Patients
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