1. Developing an Idea for a Study &
Formulation of a Research Question
By:
Mahmoud Mahmoud, MD, PhD
Prof. of Clinical Pharmacology, JFOM, KSA
Prof. of Clinical Research, AUHS, CA

2. Research question is the uncertainty
in the population that investigator
wants to resolve
How
Why
Where
When
How much
Is it
So What?

4. Anatomy and Physiology
of Clinical Research
• Anatomy: what research is made of?
• Physiology: How it works ?

5. Anatomy of Research
• Research questions (primary & secondary)
• Significance (Rationale)
• Design:
a- Observational
• 1- Cohort
• 2- Cross sectional
• 3- Case Control
( Descriptive & Analytical)
(Prospective & Retrospective)

6. b- Experimental (Interventional)
• 1- Randomization
• 2- Blindness: Single blind, Double blind
• Subjects:
1- Selections
2- Criteria
• Variables
Measurements: 1- Predictable
2- Confounding
3- Outcome

7. • Statistical issues:
• 1- hypothesis
• 2- sample size
• 3- analytic approach

8. Physiology of Research
• To study the universe through people and
phenomena
• Addressing the correct questions
• Implementing the study (carry out)
• Error of Research:

9. The scientific method
The scientific method is the best way
to solve truth from lies and delusion.
1. Observe some aspect of the
universe.
2. Invent a tentative description,
called a hypothesis, that is consistent
with what you have observed.
3. Use the hypothesis to make
predictions.
4. Test those predictions by
experiments or further observations
and modify the hypothesis in the
light of your results.
5. Repeat steps 3 and 4 until there
are no discrepancies between theory

10. Incredible Research Questions
(Silly!!!)
• Who has more bacterial flora in the colon, men or women?
• What are the facial characteristics of faithful women ?
• Optimizing the sensory characteristics and acceptance of
canned cat food: use of a human taste panel. (Journal of
Animal Physiology and Animal Nutrition)
• Effects of cocaine on honeybee dance behavior. (Journal of
Experimental Biology)
• Swearing as a response to pain. (NeuroReport)
• Pigeons can discriminate "good" and "bad" paintings by
children. (Animal Cognition)

11. How to develop a RQ ?
RQ develops from previous findings
by investigator or others.
– Scholarship: Mastering literatures
can serve as source background
– Mentors: are needed particularly for
inexperience researcher.

12. Primary and Secondary questions
• Many studies have more than one research question.
• Primary Question:
– Experiments often address the effect of intervention on
several outcomes
• Secondary Questions:
– The advantages of having several questions:
Several answers can emerge from single study
– The disadvantages of having several questions:
This will increase the complexity of the design and
implementation
– More sophisticated statistical techniques are needed

13. Being alert to new ideas and techniques
• Attend conferences
• A skeptical attitude
– Not to believe what you see but try to find better
criteria
• New technology will be helpful for new insight and
questions
• Teaching is an excellent source of inspiration

14. Criteria of Good Research
Questions
• F… I…N…E….R
•
•
•
•
•
Feasible
Interesting
Novel
Ethical
Relevant

15. Feasible
– To know the practical limits and problems of
studying a questions
• Adequate number of subjects, pilot survey is
helpful
• Adequate technical expertise for recruitment
measuring variables, analysis, putting
questionnaire.. Etc. Using consultants or coinvestigators can shape the research
• Affordable in time and money, this has to be
known and evaluated early
• Manageable scope, big scope may not be feasible.
Investigator need to narrow it

16. Interesting
– To the investigator
• Share this interest with consultant or outside
expert before writing grant.
– To the funding Agent
– To the company (pharmaceutical co)

17. Novel
– The aim is to find new information
– Reiteration of previous research is not acceptable.
– Novelty can be determined though literature review
or funding agent records
• Confirm or refutes previous finding
• Extends previous findings
• Provide new findings

18. Ethical
– Good research must be ethically accepted.
– Unacceptable risk or invasion of privacy is not
accepted
– Institution Review Board (IRB) is essential for
consultation and approval

19. Relevant
– Imagine the various outcome and the possibility that
the outcome will add to:
• To scientific knowledge
• To clinical and health policy
• To future research directions

20. Improving Research Question
• An outline (1-2 pages) will be helpful for the
investigator to clarify the ideas about the plan.
• White paper or letter of understanding
• The outline will provide basis for colleagues to react
to with specific suggestions

21. Problems and Solutions
Potential Problem
Solutions
A: The research question is not FINER
1. Not feasible:
* Too broad
- Specify a smaller set of variables
- Narrow the question
* Not enough
subjects available
- Expand the inclusive criteria
- Eliminate or modify exclusion criteria
- Add other sources of subjects
- Lengthen the time frame for entry into study
- Use strategies to decrease sample size
* Methods beyond
the skills of the
investigator
-Collaborate with colleagues who have the skills
- consult experts and review the literature for
alternative methods
-Learn the skills

22. * Too expensive
-Consider less cost study with
* fewer subjects and measurements
* less expensive measurements
* Fewer follow up visits
2- Not interesting,
novel or relevant
-Consult a mentor
- Modify research question
3- Uncertain ethical
suitability
-Consult with IRB
- Modify the research question
B- The study plan is vague
Ambiguity
-Write the research question at an early
stage
- Get specific in the one to two pages
study plan
. How subjects will be sampled
. How variables will be measured

23. Translational Research
• Translation of findings from Ivory tower to
reality
– T1: from lab to clinical studies (from Bench to
bedside)
– T2: from clinical studies to health practice
(need process and collaborators)
Lab Research
T1
Clinical Studies
Population research
T2

24. Hypothesis
• Definition:
– It is a precise testable statement of what the
researchers predict, it will be the outcome of the study.
• It is transformation of research questions into final and
most specific version to establish the basis for tests of
statistical significance.
• It summarizes the sample, design, the predictor and
outcome variables
• This usually involves proposing a possible relationship
between two variables: the independent variable (what
the researcher changes) and the dependant variable (what
the research measures).

26. Characteristics of a good hypothesis
• Simple versus complex:
– One predictor and one outcome variable
• Ex: Sedentary life style is associated with diabetes
– Combined predictor or outcome variable can be
useful
• Specific versus Vague
– To clarify subjects and the variables
• In advance versus after–the- fact
– Hypothesis needs to be state before the study not
after reviewing the data.
– The after the fact leads to over interpretation

27. Types of Hypothesis
• Null and alternative hypotheses
Null H (H0) There is no association between
predictors and outcome
Alternative H (Ha): There is association between
predictors and outcome
• One and two sided alternative hypotheses i.e.
One direction or 2 directions

28. • If your prediction was correct, then you would (usually)
reject the null hypothesis and accept the alternative.
•If your original prediction was not supported in the data,
then you will accept the null hypothesis and reject the
alternative.
•The logic of hypothesis testing is based on these two
basic principles:

29. • In research, there is a convention that the hypothesis is written in
two forms:
– the null hypothesis, or Hn, H0 and
– the alternative hypothesis (called the experimental
hypothesis when the method of investigation is an
experiment), or Ha or He (either shorthand version is
acceptable).
• Briefly, the hypotheses can be expressed in the following ways:
– The Hn states that there is no relationship between the two
variables being studied (one variable does not affect the
other).
– The Ha states that there is a relationship between the two
variables being studied (one variable has an effect on the
other).

30. • A research hypothesis (Ha) prediction is one that
states that results are not due to chance and that they
are significant in terms of supporting the idea being
investigated.
• A 'null hypothesis' (Hn) prediction is one that states
results are due to chance and are not significant in
terms of supporting the idea being investigated.

31. Types of Results
• The problem if results in the samples do not reflect the
population
– Positive
– False positive (Type I)…… Need to be zero
• Alpha (reject the null hypothesis when it is actually true,
level of statistical significance)
• Alpha of 0.05 or less
– False negative (Type II)….Need to be zero
• Beta (failing to reject the null hypothesis, when it is
actually false)
• Power (1-beta)
– Negative

33. Type 1 Error: False Positive
• Claiming that two means are not equal when in fact they
are equal. In other words, you
• reject a null hypothesis when it is TRUE.
Type 2 Error: False Negative
• Not finding a difference between two means when in fact
there is a difference. In other words, you reject a null
hypothesis when it is FALSE.

34. • Avoiding of errors entirely is difficult but
can be minimized by:
– Increase sample size
– Design
– Different measurements

35. • Strategy:
• 1- Put a scale
• 2- Precision (reproducible) of observer, instruments and
subject………. Repetition
• 3- Accuracy (confidence to measure reality)…….
Using gold standard

37. Designing Research

38. I- Designing an Observational Study
1- Cohort Study
• Powerful study
• Types: Descriptive, analytic, prospective and
retrospective
• Prospective Study: structure, strength,
weakness
• Retrospective study: structure, strength,
weakness

39. • Nested Case-control and case-cohort
studies: structure, strength, weakness
• Multiple-cohort studies and external
controls: structure, strength, weakness
• PLANNING A COHORT STUDY

40. 1-Cohort Study
Determine Incidence of Disease
Prospective
Retrospective
Nested Case-control & Case
cohort
Multiple-cohort
& External
control
Structure
Define samples
And follow
variable over
Time for future
outcome
Define samples
and follow over
time for outcome
in the PAST
Nested case Control: is cohort study (P
or R) then evaluate outcome occurrence
Vs the control
Case-Cohort:
Similar to NCC except no control cases
are selected but random samples
regardless of the outcome.
Measurements can be used for the
whole study samples
Different samples
with different risk
exposure.
In occupational and
environmental study.
Registry and census
are useful
Strength
-Powerful
-accurate
measurements of
variables in
known outcome
-Powerful
- Unbiased
- Less costly
-less time
-Useful for costly measurements
-Unbiased
-For rare exposure
and potential hazards
Weakness
-Expensive
-Inefficient in rare
outcome
-can’t evaluate
pre-post disease
-Limited control
-May not have
information
to answer the
questions
- As cohort study
-Baseline is affected by silent preclinical
diseases
-Storage of samples
-Retrospective study
lacks the recorded
information

41. 2- Cross Sectional Study
3- Case Control Study
Structure
- Select sample of population
- Measure Predictor and outcome
variable
All measurements are made at once.
- Select sample of population with
disease
- Select sample at risk free of
disease
- Measure predictor variables
Generally Retrospective
Strength
- Major source of health and habits
- Epidemiologically identify risk
information
factors
- Hypothesis determine cause and effect - Find strength between associated
factors
- Determine prevalence of
- Efficient for rare disease
disease.
- Useful to generate hypothesis
- No waiting for outcome to occur
(fast, inexpensive)
- Examine network of causal links
- Serial surveys used to determine the
changes observed at several times
Weakness
- Difficult to establish causal relation
- Does not fit for rare disease
- Can not define the time duration of
disease
- Increase risk of Bias
- Can not measure prevalence or
incidence
- Limited information

42. II- Designing Experimental
Clinical Trial
A- Randomized Blind Clinical Trial
• Powerful design for causality
• Overcome: Bias, confounders
• Blinding is effective

43. Steps
•
•
•
•
•
•
•
1- Selection of subjects
2- Measuring baseline variables
3- Randomize participants
4- Apply interventions (Placebo included)
5- Follow up Cohort
6- Measure outcome variables
7- Analyses of results

44. Selection of Subjects
• Inclusive Criteria:
• Optimize the rate of primary outcome
• Generalization with minimal high risk for feasibility
• Exclusive Criteria
• Avoid unnecessary exclusions
• Exclude non-contributors to primary outcome. And
who will be difficult to follow e.g. mental status,
harmful, treatment is ineffective
• Reasonable guided by weighing
• Restrict recruitment
• Overcome the confounding variables

45. • Sample size and recruitment strategy
• Limited # of subjects is wasteful, unethical and
misleading conclusions.
• Design a trial with:
•
•
•
•
Large #
Accessible population
Enough time
Enough money

46. Baseline variables
•
•
•
•
•
Collect tracking information (name, SS..)
Demographic data
Measure predictable variables (smoking)
Measure outcome variable (ECG)
Establish banks of materials

47. Randomization
• In 2 or more groups (placebo included)
• Avoid Bias by correct randomization for
treatment and groups
• Use Algorithm, blocked, stratified blocked
to ensure no influence of the investigator.
• Separate team my be used
• IVRS (interactive voice response system)

48. Applying Interventions
1- Placebo
• Blinding is recommended to avoid:
1- Co-intervention
2- Biased assessment of outcome
• Blinding is difficult than randomization
• Unbinding and breaking the code must be
available 24 hour (pharmacist is helpful)
• At end of the study ask subject and
investigator for the guess

49. 2- Active Drug
• It must be:
Effective, safe, highest tolerable dose
• Use a range of doses
• Choice of Control
• Consider Co-intervention for ethical reasons
1- when patient is under regular medications
2- use statistical adjustment for difference between
groups.
• Equivalence trial: under standard treatment.

50. Follow up and Adherence to
the Protocol
• Strategy for maximization:
1- Subject compliance
2- Easy intervention administration
3- Convenient visits
4- Painless study measurements
5- Encourage subject to be on trial
6- Find subject who lost follow up

51. Measure outcome
•
•
•
•
•
Clinical outcome Vs Surrogate outcome
Statistical characteristics
Number of outcome variables
Valid outcome
Adverse effect

52. Staging of Testing New
Therapy by FDA
• Pre-clinical
• Phase I: Unblind, uncontrolled, few volunteers to test
safety
• Phase II: small, randomized, controlled, blinded to test
tolerability, intensity, dose, pharmacokinetics
• Phase III: large, controlled, blinded to test effect and
outcome
• Phase IV: large, observational (post marketing
surveillance)

53. TITLE:
A prospective, randomized, openlabel, multi-center,
pharmacoeconomic evaluation,
comparing XXX to epoetin alfa in
patients with chronic kidney disease
(CKD) stage V on dialysis.
INDICATION
Anemia of chronic kidney disease
OBJECTIVES
Primary:
The primary objective of the study is to
demonstrate significant provider time
saving using XX monthly intravenous
injections compared to up to three times
weekly epoetin alfa injections for
anemia management in in-center
hemodialysis patients, while maintaining
adequate Hb control
Secondary:
Demonstrate safety of XX
TRIAL DESIGN
Prospective, randomized, open-label,
comparative, active-control multi-center
study

54. TARGET POPULATION
Patients with chronic kidney disease (stage V) on
dialysis treated with epoetin alfa for the treatment of
XX IV monthly
CKD-associated anemia
LENGTH OF STUDY
INVESTIGATIONAL
MEDICINAL PRODUCT(S)
DOSE/ ROUTE/ REGIMEN
9 months
Titration period: 7 months
Evaluation period: 2 months
Epoetin alfa
weekly dose
XX
Monthly dose
<8000 IU
120 µg/mL
8000-16000 IU
200 µg/mL
>16000 IU
COMPARATOR “DRUG” (or
STANDARD OF CARE)
DOSE/ ROUTE/ REGIMEN
360 µg/mL
Epoetin alfa 1-3/week IV per dialysis center
protocol

55. ASSESSMENTS OF:
-
EFFICACY
Co-Primary endpoints: Time and Motion and Hb change
from baseline
Time and motion will be average time spent on anemia
treatment over months 7-9 after the first study dose..
The co-primary endpoint is defined as the change in Hb
concentration from baseline to the average in months 7-9.
-
SAFETY
Safety endpoints:
oVital signs (Pre- and post dialysis: BP, heart rate, body
weight)
oECG
oAdverse events
oLaboratory parameters
oIron parameters: serum ferritin, serum iron, serum
transferrin or total iron-binding capacity (TIBC); calculated
transferrin saturation (TSAT) or percentage of hypochromic
RBCs
oHematology: hemoglobin (safety and efficacy), hematocrit,
white blood cell count, platelet count
oBlood chemistry: aspartate aminotransferase (AST),
alanine aminotransferase (ALT), creatine kinase (CK),
alkaline phosphatase (ALP), albumin, C-reactive protein
(CRP), glucose in non-diabetics, potassium, phosphorus
oAnti-erythropoietin antibody determination
oDialysis adequacy: Kt/V or urea reduction ratio (URR)

56. INCLUSION
CRITERIA
Age ≥ 18
Able to understand, provide and sign
written informed consent
CKD stage V on outpatient in-center
hemodialysis therapy
Unchanged mode of therapy for the last 3
months prior to entry into study
Anemia of CKD treated with epoetin alfa iv
3x/W
Average Hb 10-13 g/dL over last 3 months
prior to randomization. No Hb values should
be <10 or >13 g/dl during this period.
Kt/V ≥ 1.2 or URR ≥ 65%
Adequate iron status: Serum ferritin ≥ 100
ng/ml OR TSAT ≥ 20% (or percentage of
hypochromic red cells < 10%). Iron
supplement therapy, either iv or po is
allowed.

57. EXCLUSION
CRITERIA
Poor compliance with dialysis treatment,
evidenced by >2 missed treatment monthly over the
previous 3 months.
Patients hospitalized during the previous 3 months
prior to randomization for any cause except minor
surgery such as vascular graft revision.
Renal transplant
Epoetin alfa dose >300 U/kg/week.
Patients expected to change dialysis modality
over the course of the study
Immunosuppressive therapy (other than
corticosteroids for a chronic condition, cyclosporine
and monoclonal/polyclonal antibodies) in the 6
months prior to enrollment
Overt gastrointestinal bleeding or any other
bleeding episode necessitating transfusion within 3
months prior to enrollment
Hemoglobinopathies (e.g., homozygous sickle
cell disease, thalassemias of all types
Hemolysis
Active malignant disease (except non-melanoma
skin cancer)

58. - Chronic, uncontrolled or symptomatic inflammatory disease (e.g.,
rheumatoid arthritis, systemic lupus erythematosus)
- Acute infection
- C-reactive protein (CRP) > 30 mg/L
- Temporary (untunneled) dialysis access catheter
- Vitamin B12 deficiency
- Folic acid deficiency
- Uncontrolled or symptomatic secondary hyperparathyroidism
- Poorly controlled hypertension (sitting pre-dialysis systolic blood
pressure ≥ 170 mmHg – average of 2 screening values with at least one
day between measurements)
- History of seizures in previous 6 months prior to enrollment
- Current (or history of) Pure Red Cell Aplasia
- Platelets > 500x109/L
- Chronic Congestive Heart Failure (NY Heart Association Class IV)
- Myocardial infarction, severe or unstable angina, coronary artery
disease, stroke, severe liver disease within the 12 weeks prior to
enrollment
- High likelihood of early withdrawal or interruption of the study for any
reason

59. - Surgery during the course of the study or within 30 days prerandomization, unless simple surgery, i.e., simple dialysis access revision,
laser photocoagulation, etc.,
- Pregnancy or breast feeding
- Women of childbearing potential without effective contraceptive methods
- Previous treatment with XX
- Administration of another investigational drug within 6 months prior to
randomization
- Administration of erythropoietin-related compounds other than those
specified by this protocol within 6 months prior to randomization
- Known hypersensitivity to any constituent of the study or reference
medication
- RBC transfusions within 3 months prior to randomization
- Life expectancy <12 months from randomization.
- Participation in studies testing investigational devices or dialysis solutions,
unless reported to the sponsor in advance and approved by the sponsor.
- Erythropoietin-related compounds other than those specified by this
protocol within 6 months prior to randomization, during the
screening/baseline or the treatment periods