Research Methodology

By

Dr Alok MisraPost Graduate Trainee

Dept. of Organon of Medicine

Under Guidance Of

Prof L M KhanHOD, Organon of Medicine,

National Institute of HomoeopathyKolkata

Layout of observation to evidence based medicine

Empirical observation

Research

Evidence

• What is the need of Knowing Research

Methodology?

• What is Research Methodology?

• How to apply these Research

methodologies to Homoeopathy

Questions to be answered

Question No 1

What is the need of Knowing Research Methodology?

Harrisson’s Book of Practice of Medicine

The nascent field of homeopathy used blinded tests on volunteers, presaging to some extent the use of placebo-controlled trials, to prove which materials were the most able to induce or relieve symptoms.

Stephen E. Straus; Complementary and Alternative Medicine; In: Kasper Dennis L. et al; Harrison’s Principles of Intenal Medicine; New York; McGraw-Hill Medical Publishing Division; 15th edition, 2005: 68.

Davidson’s Book of Practice of Medicine

What is SR?

What is RCT?

What is Cohort study?

What is meta-analysis?

Christopher H et al. Davidson’s Principles and Practice of Medicine. Churchill Livingstone, 19th Edition 2002: 526.

Meta-analyses in Homoeopathy• Meta-analyses and Systematic reviews are the ultimate evidences in

medical science.

• There have been so many meta-analyses and systematic reviews, but except few most of them show negative results for Homoeopathy.

• Meta-analysis/Systematic reviews showing positive results for Homoeopathy:

- Linde et al; Are the clinical effects of homoepathy placebo effects? A meta-analysis of placebo-controlled trials; Lancet 1997; 350: 834-43. (This included a pooled data of 89 Randomized controlled trials)

- Kleijnen J et al; Clinical Trials of Homoeopathy; BMJ 1991; 302:316-23 (Showed positive results but reported that methodological quality of the trials were too weak to draw any definite conclusions)

- Jacobs J et al; Homoeopathy for childhood diarrhoea: combined results and meta-analysis from three randomized, controlled clinical trials; Pediatrc Infect Dis J 2003; 22: 229-34.

• Negative Meta-analysis:

- Shang A et al; Are the clinical effects of homoepathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy; Lancet 2005; 366: 726-32. (This included a pooled data of 110 RCT’s of Homoeopathy & 110 trials of Allopathy)

- Linde K et al; Impact ofquality on outcome in Placebo-controlled trials of Homoeopathy; J Clin Epidemiol 1999; 52(7): 631-6. (This was re-analyses of earlier meta-analysis with positive results)

Unanswered questions in Homoeopathy

• Hahnemann throughout his life worked hard to standardize potency & doses. Unsolved question of potency & doses are still the biggest mystery for a novice Homoeopath.

• When to prescribe in Decimal, Centesimal or Fifty millesimal scale?

• How to determine minimum dose for a individual?

Question No 2

What is Research Methodology?

Study Design

Observational Studies

Treatment studies

Analysis of RCT’s

Cohort study

Case-controlstudy

Crosssectional

study

Prospective study

Retrospective study

Randomized Controlled

study

NonRandomized

study

Systemic Reviews

MetaAnalyses

Types of Study design

Case-control study• Case-control is a type of epidemiological study design.

• Case-control studies are used to identify factors that may contribute to a medical condition by comparing subjects who have that condition (the 'cases') with patients who do not have the condition but are otherwise similar (the 'controls').

• These studies are retrospective, non-randomized nature limits the conclusions that can be drawn from them.

• Case-control studies use patients who already have a disease or other condition and look back to see if there are characteristics of these patients that differ from those who don’t have the disease.

• The study proceeds from effect to cause.

• It is useful in rare diseases or diseases about which little is known.

• It provides got base for hypothesis generation of larger Cohort study.

Cohort study or longitudinal study

• A cohort study is undertaken to obtain evidence for suspected association between cause and effect.

• A cohort is a group of people who share a common characteristic or experience within a defined period (e.g., are born, leave school, lose their job, are exposed to a drug or a vaccine, etc.).

• Cohort is identified before the advent of disease under investigation.

• Cohort study tests the hypothesis longitudinally through time.

• Cohort studies are considered the gold standard in observational epidemiology.

• The study proceeds from cause to effect.

Example

These two groups should share common characteristics like age, occupation, history to exposure to drugs & other pollutants, etc.

Study recruits

Group of smokersGroup of non-smokers (the unexposed group)

Incidence of lung cancer

Incidence of lung cancer

Followed for a period of time say 10 years

Cause

Effect

Example of Cohort Study

2009

1995

Smokers Non-smokers (Both groups are free from disease initially)

Lung Cancer

NormalLung Cancer

Normal

Cross-sectional study

• It is a type of observational study.

• Cross-sectional studies can be thought of as providing a "snapshot" of the frequency and characteristics of a disease in a population at a particular point in time.

• This type of study can be used to assess the prevalence of acute or chronic conditions in a population.

• If a significantly greater number of smokers already have lung cancer than those who don't smoke, this would support the hypothesis that lung cancer is correlated with smoking.

Cohort Study/ Cross-Sectional Study

2009

1995

Smokers Non-smokers (Both groups are free from disease initially)

Lung Cancer

NormalLung Cancer

Normal

2009

2005

1995

Smokers Non-smokers

Randomized controlled Trial (RCT)

• RCT is a gold standard technique in the field of scientific research.

• In this design the experimental population is divided into two groups, study group and control group, by a process called randomization.

• It is assured that both the comparison groups are having the same baseline characteristics like age, sex, social status, religion etc.

• Study group is the group which receives the intervention, which we intent to test, whereas control group receives placebo or a standard treatment against which we are testing the efficacy of study group treatment.

• Blinding is generally done in RCT; it may be single, double or triple blind study as per the need and feasibility of trial.

• At the end of study period the participants are decoded to analyze the results for statistical significance.

Meta-analysis & Systematic reviews

• We are often confused by research because some studies show that a therapy works and other studies shows that it doesn’t.

• To solve this problem, a recent development in research is used called ‘Systematic Reviews’ that evaluates overall results of several experiments.

• Systematic reviews are of particular value in bringing together a number of separately conducted studies, sometimes with conflicting findings, and synthesising their results.

• Meta-analysis: When Systematic reviews include statistical synthesis it is called as Meta-analysis.

• Meta-analysis should only be performed when the studies are similar with respect to population, outcome and intervention.

Research Process

Define ResearchProblem

Review Concepts

And theories

Review PreviousResearchfindings

Formulatehypothesis

DesignResearch(Including

SampleDesign)

CollectData

(Execution)

AnalyseData(Test

Hypothesisif any)

Interpretand

report

Review the literature

Research Objective• A researcher finds out enigmas of science and frames a research

problem which he attempts to resolve through his research.

• Main sources of these research problems are daily experience, academic experience, intuition or review of literature.

• Now we formulate a scientifically researchable question out of this selected research problem/topic/idea.

• These scientifically researchable questions lead us to define our research objectives.

• Research objectives should be as clear and simple as possible.

• Objectives should be projected to answer small and comprehensible questions.

• Before framing research objectives its feasibility and relevance should be ascertained.

• It should borne beforehand in our mind that what answer do we expectfor our question and what procedures we are going to adopt to achieve that answer.

Sample size

Sig

nif

ica

nc

e

Sig

nif

ica

nc

e

Sample size required

Randomization

• Randomization is a process by which the participants are allocated into intervention group or control group, to receive or not to receive intervention.

• Randomization eliminates bias and allows comparability of groups.

• It ensures that investigator has no control over allocation of participants to either study or control group, thus eliminating ‘Selection Bias’.

• Issues of randomization are very vital for the credibility of trial results.

Confounding Bias

• Randomization is done to eliminate confounding biasand to ensure similar comparison groups.

• What is confounding bias?

- These are factors though not directly related to disease or to the variables but may affect the outcome of study eg. Age, sex, social class or dependence to other drugs etc.

• Confounding bias can be eliminated by Stratified Randomization.

What all Randomization includes

Randomization

I. Random number generation

II. Restricted Randomization

III. Randomization Implementation

II a. Block Randomization

II b. Stratified Randomization

IV. RandomizationConcealment

I. Randomization generation

• Randomization sequence can be generated from a random-number table or a computerized random-number generator.

• One such computerized random-number generator is available online at:

www.randomizer.com

II. Restricted randomization

• Restricted randomization is done mainly in two ways:

II a. Blocking: to ensure that comparison groups are of approximately same size.

II b. Stratification: to ensure good balance of participant characteristics in each group.

II a. Block Randomization

• Blocking is used to ensure close balance of the numbers in each group at any time during the trial.

Eg.

• If there are 2 groups: homoeopathic (H) and placebo (P). A block size of 10 participants is assigned, then it is ensured that, 5 participants would be allocated to each arm of the trial, after every enrollment of 10 participants.

II b. Stratified Randomization

• By chance, particularly in small trials, study groups may not be well matched for baseline characteristics, such as age and stage of disease etc.

• Stratification ensures that the numbers of participants receiving each intervention are closely balanced within each stratum. Eg. If trial is stratified for smokers & non-smokers, then stratification ensures that no. of smokers & non-smokers are balanced in all the intervention groups.

• Stratified randomization is achieved by performing a separate randomization procedure within each of two or more subsets of participants (for example, those defining age, smoking, or disease severity).

• Stratification requires blocking within strata.

……cont.

Stratified Randomization

Eg.

• If we stratify patients according to the severity of disease i.e. mild, moderate and severe. By block randomizing within this strata we ensure equal number of participants in each intervention group for all severity of disease.

• If Suppose 100 participants of different intensities of a given disease are enrolled:

Intervention group Placebo Group

Mild (n=50) 25 25

Moderate (n=30) 15 15

Marked (n=20) 10 10

III. Randomization implementation

• It should be clearly stated that:

- who generated the allocation sequence,

- who enrolled participants, and

- who assigned participants to their groups.

IV. Allocation concealment

• Decentralized or “third-party” assignment is especially desirable.

• Many good approaches to allocation concealment incorporate external involvement.

• Use of a pharmacy or central telephone randomization system are two common techniques.

• Manuscript must include steps taken to conceal randomized allocation.

Allocation concealment prevents foreknowledge of investigator regarding assignment of subjects to either of the intervention or control group. Allocation concealment seeks to prevent selection bias.

Blinding procedure

The blind method is a part of the scientific method, used to prevent research outcomes from being influenced by either the placebo effect or the observer bias.

There are three sources of bias:

First: there may be bias on the part of the participants, who may feel better or worse if they knew the form of treatment they are receiving, this is known as ‘Subject bias’.

Secondly: there may be bias on the part of observer in assessing participants’ condition if they know beforehand the therapy to which the participants’ have been subjected, this is known as ’Observer bias.’

Thirdly: there may be bias in evaluation by evaluator. To rule out these objective problems a technique known as blinding is adopted.

Type of blinding

• There are 3 types of blinding methods used:

- Single-blind: Only participants were blinded.

- Double-blind: Both participants & Investigators were blinded.

- Triple-blind: Participants, investigators & Statistician were blinded.

• The opposite of a blind trial is an “Open” or “Open label trial”

Characteristics of blinding

• The similarity of characteristics of treatments (for example, appearance, taste, and method of administration) should be same for both the intervention as well as control group.

• Efforts taken to blind the patient, prescriber and evaluator must be stated clearly and all efforts should be made to achieve effective blinding.

• In single blind study open prescriptions should never be given to patients, which may reveal prescriptions.

• In double blind study it should be assured that how both patient and investigator shall be blinded about what patient gets (individualized medicine or placebo).

• In a triple blind study, allocation should not be decoded till analysisfor the efficacy of drugs have been completed.

• So, far possible researcher should use validated and reliable assessment tool which is sensitive to changes in participants’ condition.

• It requires a complete study to validate a scale.

• Scale should be sensitive enough to assess the slightest change in patients’ condition.

• Outcome measures are tools used to assess change in a patient over time.

• They measure change in meaningful areas of a person’s life in a way that informs collaborative decisions about treatment.

Outcome measures

• There are so many disease-specific validated scales available in the scientific world eg.

- Depression:

Beck Depression Inventory (BDI)

Hamilton Depression Rating Scale (HDRS)

- Attention deficit Hyperactivity Disorder

Conner’s Parent Rating Scale (CPRS)

Vanderbilt Teacher Rating Scale (VTRS)

- Acute Otitis Media

Acute Otitis Media – Severity of Symptoms (AOM-SOS) Scale.

• There are endless list of disease specific scales.

Disease-specific Scale

• There are so many non-specific scales which can be used in cases where disease specific scales are not available.

• Few such scales, most widely used through out the scientific world, are

Visual Analog Scale (VAS),

Clinical Global Impression (CGI) Scale,

Facies Pain Scale etc.

Disease non-specific Scale

• Quality of Life (QOL) assessment is one of the most important, non-specific but sensitive, ‘Subjective’ scale to assess general sense of well being even before the improvement of pathological parameters.

• It is more specific because individual himself perceives the condition and score it on QOL scale.

• This assessment of general wellbeing is more in congruence with Hahnemann’s concept (§161) of wellbeing.

• So, QOL would be best utilized in Homoeopathy to assess the general sense of wellbeing.

• Now a days we do have disease specific QOL also available like for HIV, Tuberculosis, Uterine fibroid etc.

Quality of Life (QOL)

Question no 3

How to apply these Research

methodologies to Homoeopathy

Drug Proving

• Drug proving is the best model for Double blind placebo controlled trials.

• In this trial, medicine to be proved are filled in half of the medicine bottle & rest half of the bottle are filled with identical placebo (identical in all respect i.e. color, taste and smell).

• All these bottles are coded and these coding details are concealed and maintained centrally.

• Healthy participants are randomized, preferably stratified for age, sex and economic status, to receive either medicine or placebo.

• After completion of the drug proving, medicines are decodedand symptoms are evaluated for there statistical significance.

Clinical Research

• Homoeopathic tenets should never be compromised for Research methodologies.

• Research methodologies should be styled as per the requirements of Homoeopathic Philosophy.

Disease related study Step 1: To screen potential patients of the disease in question.

Step 2: To confirm the diagnosis.

Step 3: Confirmed patients shall be sent to the investigator for thorough case taking, individualization and prescription of most indicated medicine to all patients irrespective of their group allocation.

Step 4: This investigator shall be totally unaware of the group allocation of the patient; he’ll send the prescription to a pharmacy.

Step 5: Pharmacist shall have no contact with the investigator. He’ll randomize the patient as per the random number chart provided to him.

Step 6: As per the randomized allocation he’ll supply either placebo or the prescribed medicine to the patient. Both medicine and placebo should be identical and indistinguishable.

Step 7: Both patient as well the investigator are unaware of the group allocation. So, in follow-up visits investigator will assess the patient without any prejudice & bias.

Step 8: After completion of the study, patients shall be decoded to statistically analyze difference in improvement index of placebo & individualized homoeopathic medicine group.

Drug related studySuppose we are testing for Rhustox in osteoarthritis:

Step 1: To screen patient out patients of Osteoarthritis.

Step 2: Cases:

- finally diagnosed for Osteoarthritis and;

- After forming totality of symptoms & individualizing the case if it indicate for Rhustox, then the case shall be enrolled in study.

Step 3: Now all patients shall be randomized to receive either placebo or Rhustox in blinded fashion.

Step 4: Patients shall be followed up for stipulated time.

Step 5: After completion of study period patients shall be decoded to analyze the results.

• Such type of study pose a problem of screening large number of patient to complete the sample size.

Working Methodology from a trial on ADHD

Homoeopathic evaluation of each patient

Prescription of individualized Homoeopathic medicine

Homoeopathic prescription will be communicated by fax or email to a Pharmacy

Pharmacist randomized the prescription to either placebo or verum & deliver the same by post

In follow-up visit investigator will assess the patient condition and make prescription as per the need of case

In this way

both patient &

investigator are

blinded about

group allocation

Initial randomization

will be maintained

After completion of study follow-up data will be analysed and after complete analysis codes will be broken

Jacobs J et al; Homeopathy for Attention-Deficit/Hyperactivity Disorder: A Pilot Randomized-Controlled Trial; J Alt Complement Med; 2005,11(5): 799–806

Blinding procedureSTEP 1: There shall be separate box for each medicine.

STEP 2: Each box shall be labeled with name of particular medicine, kept in that box.

STEP 3: Each box shall be containing 20 identical bottles, 10 bottles of placebo and 10 bottles of the single medicine in 30C potency.

STEP 4: Each bottle shall be labeled with its pre assigned code. These codes shall be decoded only after final evaluation of the study.

STEP 5: Each medicine/ medicine box shall be provided with separate randomization chart.

STEP 6: After selection of medicine, patient shall be randomized using chart for his indicated medicine to identify the code of his bottle.

STEP 7: Coded bottle shall be sort for, in medicine box.

STEP 8: This bottle may contain active homoeopathic medicine or placebo, which is neither known to investigator or the patient.

National Center for Biotechnology Information+

U.S. National Library of Medicine+

U.S. National Institute of Health (NIH)

www.pubmed.com

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