By:

Mahmoud Mahmoud, MD, PhD

Prof. of Clinical Pharmacology, JFOM, KSA

Prof. of Clinical Research, AUHS, CA

Developing an Idea for a Study & Formulation of a Research Question

How

Why

Where

When

How much

Is it

Research question is the uncertainty Research question is the uncertainty in the population that investigator in the population that investigator

wants to resolvewants to resolve

So What?

Anatomy and Physiologyof Clinical Research

• Anatomy: what research is made of?

• Physiology: How it works ?

Anatomy of Research• Research questions (primary & secondary)

• Significance (Rationale)

• Design: a- Observational

• 1- Cohort

• 2- Cross sectional

• 3- Case Control( Descriptive & Analytical)

(Prospective & Retrospective)

b- Experimental (Interventional)• 1- Randomization

• 2- Blindness: Single blind, Double blind

• Subjects:1- Selections 2- Criteria

• VariablesMeasurements: 1- Predictable

2- Confounding

3- Outcome

• Statistical issues:• 1- hypothesis

• 2- sample size

• 3- analytic approach

Physiology of Research• To study the universe through people and

phenomena

• Addressing the correct questions

• Implementing the study (carry out)

• Error of Research:

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 and experiment and/or observation.

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)

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.

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

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

Criteria of Good Research Questions

• F… I…N…E….R• Feasible

• Interesting

• Novel

• Ethical

• Relevant

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 co-investigators 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

Interesting– To the investigator

• Share this interest with consultant or outside expert before writing grant.

– To the funding Agent– To the company (pharmaceutical co)

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

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

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

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

Problems and SolutionsPotential ProblemPotential Problem SolutionsSolutions

A: The research question is not FINERA: The research question is not FINER

1.1. Not feasible:Not feasible:

* Too broad* Too broad - Specify a smaller set of variables- Specify a smaller set of variables- Narrow the question- Narrow the question

* Not enough * Not enough subjects availablesubjects available

- Expand the inclusive criteriaExpand the inclusive criteria- Eliminate or modify exclusion criteriaEliminate or modify exclusion criteria- Add other sources of subjectsAdd other sources of subjects- Lengthen the time frame for entry into studyLengthen the time frame for entry into study- Use strategies to decrease sample sizeUse strategies to decrease sample size

* Methods beyond * Methods beyond the skills of the the skills of the investigatorinvestigator

-Collaborate with colleagues who have the skillsCollaborate with colleagues who have the skills- consult experts and review the literature for consult experts and review the literature for alternative methodsalternative methods-Learn the skillsLearn the skills

* Too expensive* Too expensive -Consider less cost study withConsider less cost study with * fewer subjects and measurements* fewer subjects and measurements * less expensive measurements* less expensive measurements * Fewer follow up visits* Fewer follow up visits

2- Not interesting, 2- Not interesting, novel or relevantnovel or relevant

-Consult a mentorConsult a mentor- Modify research questionModify research question

3- Uncertain ethical 3- Uncertain ethical suitabilitysuitability

-Consult with IRBConsult with IRB- Modify the research questionModify the research question

B- The study plan is vagueB- The study plan is vague

AmbiguityAmbiguity -Write the research question at an early Write the research question at an early stagestage- Get specific in the one to two pages Get specific in the one to two pages study planstudy plan . How subjects will be sampled. How subjects will be sampled . How variables will be measured. How variables will be measured

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)

T1 T2

Lab Research Population researchClinical Studies

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).

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

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

• 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:

• 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).

• 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.

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

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.

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

• Strategy:• 1- Put a scale

• 2- Precision (reproducible) of observer, instruments and subject………. Repetition

• 3- Accuracy (confidence to measure reality)…….

Using gold standard

Designing Research

I- Designing an Observational Study1- Cohort Study

• Powerful study

• Types: Descriptive, analytic, prospective and retrospective

• Prospective Study: structure, strength, weakness

• Retrospective study: structure, strength, weakness

• Nested Case-control and case-cohort studies: structure, strength, weakness

• Multiple-cohort studies and external controls: structure, strength, weakness

• PLANNING A COHORT STUDY

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 outcomein the PAST

Nested case Control: is cohort study (P or R) then evaluate outcome occurrenceVs the controlCase-Cohort: Similar to NCC except no control casesare 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

1-Cohort StudyDetermine Incidence of Disease

2- Cross Sectional Study 3- Case Control Study

Structure - Select sample of population- Measure Predictor and outcome variableAll measurements are made at once.

- Select sample of population with disease- Select sample at risk free of disease- Measure predictor variablesGenerally Retrospective

Strength - Major source of health and habits information- Hypothesis determine cause and effect

- Determine prevalence of disease.- No waiting for outcome to occur (fast, inexpensive)- Examine network of causal links- Serial surveys used to determine the changes observed at several times

- Epidemiologically identify risk factors- Find strength between associated factors- Efficient for rare disease- Useful to generate hypothesis

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

II- Designing Experimental Clinical Trial

A- Randomized Blind Clinical Trial

• Powerful design for causality

• Overcome: Bias, confounders

• Blinding is effective

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

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

• 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

Baseline variables

• Collect tracking information (name, SS..)

• Demographic data

• Measure predictable variables (smoking)

• Measure outcome variable (ECG)

• Establish banks of materials

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)

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

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.

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

Measure outcome

• Clinical outcome Vs Surrogate outcome

• Statistical characteristics

• Number of outcome variables

• Valid outcome

• Adverse effect

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)

TITLE: A prospective, randomized, open-label, 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 controlSecondary:Demonstrate safety of XX

TRIAL DESIGN Prospective, randomized, open-label, comparative, active-control multi-center study

XX IV monthly

TARGET POPULATION Patients with chronic kidney disease (stage V) on dialysis treated with epoetin alfa for the treatment of CKD-associated anemia

LENGTH OF STUDY 9 monthsTitration period: 7 monthsEvaluation period: 2 months

INVESTIGATIONAL MEDICINAL PRODUCT(S)DOSE/ ROUTE/ REGIMEN

COMPARATOR “DRUG” (or STANDARD OF CARE)DOSE/ ROUTE/ REGIMEN

Epoetin alfa 1-3/week IV per dialysis center protocol

Epoetin alfaweekly dose

XXMonthly dose

<8000 IU 120 g/mL

8000-16000 IU 200 g/mL

>16000 IU 360 g/mL

ASSESSMENTS OF:

- EFFICACY Co-Primary endpoints: Time and Motion and Hb change from baselineTime 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)oECGoAdverse eventsoLaboratory parametersoIron parameters: serum ferritin, serum iron, serum transferrin or total iron-binding capacity (TIBC); calculated transferrin saturation (TSAT) or percentage of hypochromic RBCsoHematology: hemoglobin (safety and efficacy), hematocrit, white blood cell count, platelet countoBlood chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), alkaline phosphatase (ALP), albumin, C-reactive protein (CRP), glucose in non-diabetics, potassium, phosphorusoAnti-erythropoietin antibody determinationoDialysis adequacy: Kt/V or urea reduction ratio (URR)

- INCLUSION CRITERIA

Age ≥ 18 Able to understand, provide and sign written informed consentCKD stage V on outpatient in-center hemodialysis therapyUnchanged mode of therapy for the last 3 months prior to entry into studyAnemia of CKD treated with epoetin alfa iv 3x/WAverage 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.

- 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 transplantEpoetin alfa dose >300 U/kg/week. Patients expected to change dialysis modality over the course of the studyImmunosuppressive therapy (other than corticosteroids for a chronic condition, cyclosporine and monoclonal/polyclonal antibodies) in the 6 months prior to enrollmentOvert gastrointestinal bleeding or any other bleeding episode necessitating transfusion within 3 months prior to enrollmentHemoglobinopathies (e.g., homozygous sickle cell disease, thalassemias of all typesHemolysisActive malignant disease (except non-melanoma skin cancer)

- 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

- Surgery during the course of the study or within 30 days pre-randomization, 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