Writing up a Clinical Research Proposal Dr. Thaw Dr. Thaw Zin

Writing up a
Clinical Research Proposal
D r. Thaw Z in
M B B S, M M edSc, F A CTM , PhD (N SW )
Clinical Pharm acologist
A ssistant Professor/F M H S, U TA R
Before
Law of cause & effect:
In reality – not so simple because outcome
can be masked by -
-Associated
factors (yellow
fingers)
-Natural
process of disease/homeostasis
-Confounding
factors
-Bias
(systematic error)
-Chance
(random error)
-Outliers
Such factors needs to be controlled in order to come
to a valid & meaningful interpretation
Understanding research methods is necessary to
overcome these barriers to reach a valid conclusion
After
Factors that needs to be controlled - Threats
Reliability – consistency of measurements
Validity – strengths of conclusions, inferences or prepositions
Study design
Statistical power
Overcome barriers – Increases the Strength of Analysis
– randomized or true experimental design/models
randomization- simple, systematic, stratified , etc.
blinding –single/
double/ triple
controlling– positive/negative/placebo
– quasi-experimental
design
– non-experimental
design (quick
& dirty/simple research)
– sample size
– effect size (p value)
– error (alpha; power/beta)
Idea
generation
Problem
solving
Research is the cornerstone of any science. Clinical Research is an
organized, structured, purposeful attempt to gain knowledge about
a suspected relationship in a clinical setting (patients)
Cause
Systematic
collection
Analysis
Interpretation
Effect
Funding
ANSWER(s)/
Presentations
Research
Culture/
Collaborators
Creativity
RESEARCH & DEVELOPMENT
Education – the principle goal of today’s education is to create men who are
capable of new things, not simply repeating things what others have done.
A generation of creative, inventive & discoverers.
Jean Piagett
Self development – Doctors today need more than knowledge of medicine &
good clinical ability to be successful. The ability to write well, develop a grant
proposal that is fundable, put up a report of research that is worth publishing,
prepare a paper or presentation that is well received
MERIT.
Resource development – a good researcher attracts grants & collaborators.
A true leader never leads, it is the people that follow him. Leave your name
engraved in the sands of time & not on your grave
Research Training Grant (WHO/TDR): [1994-1998], 1998], Study on pharmaco-
kinetics of mefloquine isomers & their relationship with efficacy, toxicity
& development of resistance. UNDP/World Bank/WHO Special Program
for Research & Training in Tropical Diseases, WHO, Geneva Switzerland.
Research Grant pertaining to Development of Poison Control Centre,
Myanmar (WHO/SEARO): [2001-2003]. 2003]. Phase I - Study of clinico-
epidemiological pattern of poisoning & risk of fatality among poisoning
cases at Yangon General Hospital. Regional Grant.
Research Capability Strengthening Grant (WHO/TDR/RCS): [2002-2005], 2005],
Study of social and clinico-pharmacological factors likely to contribute to
treatment failure in pulmonary tuberculosis patients, , Institutional Capa-
bility Strengthening on Tuberculosis Research in Myanmar. UNDP/World
Bank/WHO Special Programme for Research and Training in Tropical
Diseases, WHO, Geneva Switzerland.

X 1,000 U$
45
40
35
30
25
20
15
10
5
0
35
30
25
20
15
10
5
0
NPCC
PARA
INFO
NUTR
EPI
NUMED
VIRUS
EXMED
BACT
ENTO
2004-20052005
2003-20042004
IMMUN
HSR
EPI
CRD
PATHO
PHARM
BOD
PHYSIO
NUMED
EXMED
NBRC
NUTR
ENTO
NPCC
BACT
VIRO
IMMU
INFO
STAT
HSR
BIOCHEM
CRD
MK-Review of WHO RB (DMR-LM) - Oct 2004
Southeast Asian National Research Program (SEANREP) Grant [2004-
2006], Study on Traditional Medicine Culture & Impact upon Institutional
Health Care in Myanmar, Toyota Foundation, Tokyo, Japan
Programme/Institutional Grant (WHO/APW/NCD): [2006-2007], 2007], Cost-
effectiveness of treatment approaches used for cervical & uterine
cancers at Central Women Hospital & Oncology Ward, YGH. WHO SEARO
Small Research Grants for Patient Safety [2009-2010], 2010], Detection of
counterfeit & substandard drugs using simple techniques. World Alliance
for Patient Safety, WHO/HQ, Geneva, Switzerland
Regional Grant: [2009-2011]. 2011]. Assessing effectiveness of Sapium insigne
in detoxification of opiate addicts by integrated Traditional Medicine
Approach, WHO/SEARO
Problem
Solution
I keep six honest serving-men,
(They TAUGHT me ALL I know);
Their names are WHAT & WHY & WHEN,
And HOW & WHERE & WHO.
Rudyard Kipling
What – research target/topic
Why – research rationale/objectives
When – research planning/activity
How – research design & approach
Where – research area & implementation
Who – research outcome & utilization
ACTION/
APPLICATION
Idea
Generation
TITLE
Of all my verse, like not a line;
But like my title, for its not mine;
That title from a better man I stole;
Ah, how much better, had I stol’n the whole
FIND FOCUS DEVELOP
An ordinary person see things as they are and ask - WHY
R o bert L o u is S tevenson
A genius dream things as they never were and ask - WHY NOT
G eorge B ernard Shaw
If something is not part of a solution, then it is part of a problem
Which is the best to your knowledge-
- There is yet, NO solution or answer (what is = what should be)
- There are MANY likely conflicting answers
- Cannot be worked out by common sense
ACT
- Ignoring it is NOT the best answer
Describe a phenomenon to others to convince them to do something
Develop a method or a tool that can help solve the problem
Develop a policy or guideline to solve future problems
Discover/learn something new – aimed at advancement of knowledge

Disease-related factors
Inappropriate
patient selection
Late diagnosis &
treatment
Poor in vitro
mapping
Poor drug
storage
facilities
High parasite
density
Wrong selection
of drugs
Use of expired
drugs
Decrease
parasite
sensitivity
Genetic
disorders
Increase in Malaria
Treatment Failure
Cases at the DSGH
Poor quality of
drugs
Counterfeit &
substandard drugs
Drug-related factors
Non/low
immunity
Inappropriate
drug
combination
Patient related factors
Area of malaria
contact
Poor patient
compliance
Inavailability of
alternative
treatment
Associated
factors
age/pregnancy
Poor
understanding of
treatment
Poor knowledge of
disease
Previous
treatment
received
1. Title
2. Investigator(s)
3. Introduction / Rationale / Justification
4. Objectives
5. Materials and methods
6. Data collection and analysis
7. Requirement
8. Time Frame
9. Budget estimate and its breakdown
10. References
Title
Brief, descriptive, specific, proper syntax order
Investigator(s)
Relevant qualifications – degree, participatory, responsibility,
background experience
Resistance
– Gene mutation(s) or amplification that
modify drug-target (enzymes) or drug-
transporter functions or affinities
Introduction / Rationale / Justification
Historical background – think globally, act locally
Existing knowledge – what is known
Gaps in knowledge – what is required
Scientific merit – what is expected of the study
Potential impact & utilization – target beneficiaries & end-users
Treatment failure
Immunity
– Young children
– Pregnant women
– Migrants, expatriates
Drug: Pharmacology
– pharmacokinetics
– pharmacodynamics
– Pharmaceutics
Pharmacological
Factors affecting
Drug Resistance
Principal Investigator
Prof Col Marlar Than, Consultant Physician/Project Manager, DSGH
Co-investigators
Dr. Thaw Zin, Director (Research)/Clinical Pharmacologist, DMR.
Dr. Saw Lwin, Director, Vector-borne Disease Control, DOH
Dr Myat Phone Kyaw, Dy Director/Medical Parasitologist, DMR
Dr. Leonard Ortega, Project Advisor, WHO Regional Office, Myanmar
Capt. Aung Zaw Oo, Medical Officer, 5 th Medical Battalion, Karen State
Dr. Aye Yu Soe, Medical Officer, Clinical Research Unit (Malaria), DSGH
Ms. Moe Moe Aye, Research Officer/Chemical Analyst, NPCC, DMR
Dr. Khin Chit, Deputy Director/Project Organizer, NPCC, DMR
Spread of Artemisinin Resistance in SE Asia Region

Which area of study should be given priority
What is meant to be achieved at the end of the study
S - Specific
Criteria – be ‘SMART’
M – Measurable
A – Achievable
R – Relevant
T – Time-bound
Urgency
Feasibility
Cost
Political/ethical
acceptability
Duplication
General Objective
To assess therapeutic efficacy of first & second line drugs for the
treatment of uncomplicated P. falciparum malaria
Specific Objectives
To measure clinical & parasitological efficacy by assessing patients with
Early Treatment Failure (ETF), Late Clinical Failure (LCF), Late
Parasitological Failure (LPF), or with an Adequate Clinical &
Parasitological Response (ACPR) as indicators of efficacy;
To differentiate recrudescence from new infections by Polymerase
Chain Reaction (PCR) analysis;
To evaluate the incidence of adverse events;
To formulate recommendations & to enable Ministry of Health to make
informed decisions about possible need for updating of Current
National Antimalarial Treatment Guidelines.
Man power
Supervisor(s), PGstudents, collaborators, hospital staff, laboratory
staff, technical assistants, field workers, etc.
Money/ Funds
WHO/UNDP/World Bank/UNICEF/JICA/Foundations/IAEA/KOICA/
DMR grant/Wellcome Trust/Industry or out from your own pocket
Materials
Subjects, samples, laboratory facilities - availability, accessibility,
timing, procedures & permission, storage, transport, computer
facilities, etc.
Methods
Development, standardization, validation (reliability criteria)
Time frame – need to finish, extendibility, interim analysis
Research
Conflicts
Administrator
TLC
Research Models:
Intervention
- Deficit
- Distrust
- Conflict
- Conformity
Researcher
Cause
Valid data
Physician
Patient Outcome care
Developing a
Research Team
F = Flexible/Fair
R = Responsible
E = Energetic
A = Available
K = Knowledgeable
T = Together
E = Everybody
A = Achieves
M = More
“I learn from my patients and my dear colleagues,
what I can never learn from books or my teachers”
Henry Brook Adams
Correction & Critics:
If well received,
Will save our future,
A lot of grief.
For, as the twig is BENT;
So grows the tree.
E u gene P atterson
Once done; cannot repeat on patients

• Inj artemether:
Quality is NEVER an accident
It is ALWAYS the result of
*High intension, *sincere effort,
*Intelligent direction, & *skillful execution
Standards
Principal investigator
Supervisor/facilitator
Prestige
Collaborators
Technical staff
• Inj artesunate:
• Inj quinine:
• Tab artemether:
• Tab artesunate:
• Mefloquine:
• Quinine:
• Chloroquine:
• Primaquine
• Doxycycline:
Trial strategy
One arm, comparative study, using parallel group design
Non-inferiority trial if comparison of 2 highly effective medicines
Superiority if comparison of highly effective vs failing medicine
Study site
Defence Services General Hospital (DSGH)
Fifth Medical Battalion, Mawlamyaing (primary drainage site)
Sentinel site network around FMB (secondary drainage site)
Study population
Patients all age group diagnosed with uncomplicated P. falciparum
malaria & having given or whose parents or guardians have given
an informed consent for study inclusion and assent in children as
appropriate.
Inclusion criteria
All patients over 6 months with mono-infection with P. falciparum
Detected at microscopy, parasite count between 1000–100
000/μl
Axillary T°≥ 37.5°C or history of high fever during last 24 hours
Ability to swallow oral medication; without h/o allergic to medicine
Ability & willingness to comply with the study protocol
Agreed written informed consent from patient/parent/guardian, in
case of children.
Exclusion criteria
General danger signs of severe & complicated falciparum malaria
Mixed infection with another Plasmodium species
Taken any antimalaria drug within the last week
Any associated diseases which can act as confounding factors
Women with positive pregnancy test or who are breastfeeding
Anticipated population proportion (P), confidence level 95%
d 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50
0.05 73 138 196 246 288 323 350 369 380 384
0.10 18 a 35 a 49 a 61 72 81 87 92 95 96
a
In order to be representative, a minimum of 50 patients should
always be included.

Antimalaria drug administration
First & second line drugs, regime according national guidelines
Preferably fasting/light diet; drug administered with 200 mL water
Clearance required from National/DMR Committee on Medical Ethics for
studies involving human subjects
Timing & duration of study
During malaria transmission (rainy) season; May to November
2008/2009
Timed-blood samples collected at specified intervals as scheduled
Follow-up of 28 days minimum
Tools for data validation/correction
Genotyping to distinguish between recrudescence & re-infection
In vitro sensitivity test & molecular markers for drug resistance,
Pharmacokinetic study for bioavailability & dosages assessment
Pharmaceutical analysis for quality assurance of drugs used
Early Treatment Failure (ETF)
– Development of danger signs or severe malaria on D1, D2, D3 in presence of parasitemia
– Parasitemia on D2 higher than D0
– Parasitemia on D3 > 25% count D0
– Parasitemia on D3 with axillary temperature > 37.5°C
Late Clinical Failure (LCF)
– Development of danger signs/severe malaria after Day 3 in the presence of parasitaemia
without previously meeting any of criteria of early treatment failure;
– Presence of parasitaemia & axillary temperature > 37.5°C on any day from Day 4 to Day
28, without previously meeting any of criteria of early treatment failure
Late Parasitological Failure (LPF)
– Presence of parasitaemia on any day from Day 7 to Day 28, axillary temperature < 37.5°C,
without previously meeting any of criteria of early treatment failure or late clinical failure
Adequlate Clinical & Parasitological Response (ACPR)
– Absence of parasitemia on Day 28 irrespective of axillary temperature without previously
meeting any of criteria of early treatment failure or late clinical or parasitological failure
Procedures
Clinical
Assessment
Day 0 Day 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day 28 Any other
day
X X X X X X X X X
Temperature X X X X X X X X X
Blood slide for
Parasite count
X (X) X X X X X X (X)
Hb & Hct (X) (X) (X) (X)
Urine sample
(X)
Blood for PCR X X X X X X (after
Day 7)
Treatment
Drug to be tested X X (X)
Rescue treatment (X) (X) (X) (X) (X) (X) (X) (X)
Molecular markers of drug resistance
• Compulsory for TET (longer follow-up)
• Sampling D0, D7, D14, D21, D failure,
D28
• Genotyping only D0 and D failure
• Consensus on standardization during
co-sponsored WHO MMV meeting
– Sampling scheme
– Methods of blood sampling and sample
storage
– Genotyping strategy
– Analyses and outcome classification
– Quality control
– Genotyping of P. vivax
Compound class Drugs Gene Codon with
AA change
4-aminoquinolines Chloroquine pfcrt 76
pfmdr 186 (1034, 1042, 1246)
Antifolate Pyrimethamine dhfr 108, 51, 59, 164
Sulfadoxine dhps 436, 437, 540, 581, 613
Amino-alcohols Mefloquine pfmdr1 copy number
Sesquiterpene lactone Artemisinin pfmdr1 copy number
derivatives pfATPase6
Naphtoquinine Atovaquone cyt b

Pharmacokinetic Analysis
Drug-plasma concentrations of artesunate and DHA will be
performed using a LCMS & HPLC-UV
methods respectively.
Pharmacokinetic data - analyzed using WinNonlin Professional
(Pharsight Corporation, Mountain View, CA).
Population Pharmacokinetic/dynamid method applied using
nonlinear mixed-effects effects models
Pharmacokinetic/dynamic linkage will be explored using logistic
regression analysis of treatment success or failure
Statistical Analysis
All statistical analyses will be performed using SPSS (IBM ver. 4.1)
Time to parasite & fever clearance will be estimated using Kaplan-
Meier survival analysis, & linear log regression of serial log-parasite
counts in each patient.
First Year
Second Year
Project activities
Planning phase
-Consultant
-Training
-Data
collection
1 st
Quarter
2 nd
Quarter
3 rd
Quarter
4 th
Quarter
1 st
Quarter
2 nd
Quarter
3 rd
Quarter
4 th
Quarter
Implementation
-Trials/Experiments
-Surveys/Treatments
-Intervention
/
Monitoring
-Post-intervention
Data Analysis
Report Writing
BUDGET
Personnel
Labour cost
Patient care
Travel
Equipments & supplies
Sample storage & transfer
Chemicals/Medicines
Trainings/workshop
Consultants
Data processing
First Year
(US$)
1200.00
1400.00
800.00
700.00
7500.00
700.00
1200.00
400.00
-
Second Year
(US$)
800.00
800.00
800.00
1000.00
1500.00
200.00
-
1000.00
-
Total
(US$)
2000.00
2200.00
1600.00
1700.00
9000.00
900.00
1200.00
400.00
TOTAL 13,900.00 6,100.00 20,000.00
REFERENCES
When will
research END
Implement
Set Action
Plan
Identify
Cause
Problems
Problems
Identify
Cause
Implement
Set Action
Plan
Research, Development and Problem Solving Cycle

100.0
%T
50.0
0.0
Std A-001
A-01
A-012
A-013
A-018
A-020
A-024
-50.0
4000.0
3000.0
2000.0
1500.0
1000.0
500.0
ARTE13
1/cm
Superimposition of FT-IR Spectrum of ArtesunateTablets
Knowledge gives individuals &
organizations the capacity to
‘ACT’
1. Reality to Data
2. Data to Information
3. Information to Knowledge
4. Knowledge to Wisdom
Series of transformations
Knowledge
Data
Closing the “Know-do” Gap
Context
Independence
Useful Information
Understanding
relations
Understanding
principles
Knowledge to ACT
Understanding
patterns
Performance
Guidelines
Understanding
Comparative bioequivalence between different artesunate brands
available in Myanmar
Sample Uniformity of
weight pH value
(1%) Disinte-
gration
timeQualitative
Identific-ation
ationAssay
A-001
2.7 -3.9 5.1 110 A-010
1.2 -1.8 4.6 3 102 0.7 -1.3 4.9 4 112 A-013
2.8 -2.5 5.4 5 104 A-018
1.6 –3.5 6.4 60 7 A-020
0.5 -0.6 4.1 2 108 A-012
2.6 -5.1 6.3 26 15 Artesunate (Standard) 2.7 -3.2 % 4.0 5min + 100 % A-024
Dihydroartemisinin concentration
Parasite biomass
Piperaquine concentration
Residual parasites
Predicted efficacy of DHA-PQ Incorporating of drug
pharmacokinetic & dynamic clearance of parasite through
the use of Mixed-effect Modeling (Kill Curve)
Questions, discussions, critics, comments ….
46

“H ow foolish I w ou ld be, to stare w ith aw e at th e ligh t of th e can d le,
W h en I can , in fact, beh old - th e rad iance of th e su n ”
Longfellow