Clinical Research Designs: A Review Pradeep Battula 1*, T Muneeswar Reddy 2, Kali Chandra Shekar 2, Divya G 1, Dhanunjaya S 1, Durga Prasad T S 1, Sridhar C 1, Ranganayakulu D 1 Abstract: Research study design is defined as a plan, protocol, strategy or scheme of a study. The studies are useful to find out the unidentified effects and things concerning the drugs and diseases. To solve the troubles regarding the drugs and diseases a suitable research study design should be selected. The choice of study is based on the purpose of the study. And well designed study will obviously recognize an exposure and an outcome. The research study designs are classified into two types, one as observational study, second as interventional and both studies further classified into different types. Observational studies will be completed in soon or quickly when compared with the interventional studies, but observational studies are useful only for to set the hypothesis whereas interventional studies useful to test hypothesis and to identify the causes. Apart from these two studies other studies like Nested hybrid study designs, different Randomized study designs are there to find out the answers for the particular questions regarding the drugs and diseases. Each study has their own advantages and disadvantages in terms of the money and time. However, understanding of the various studies is important. INTRODUCTION Research study designs and pharmacoepidemiological studies are the studies to identification of reasons for diseases, drug effects and uses. Research study design is defined as a plan, protocol, strategy of a study and Pharmacoepidemiology means the application of epidemiological reasoning (Analysis), methods and knowledge to the study of the uses and effects (Beneficial and Adverse) of drugs in human population. [1, 2] These studies are connection among pharmacology, pharmacy, bio-statistics and demographic social sciences. [3] To improve the patient care new drugs are evolving and entered into the market with unknown effects as well as old drugs too. And diseases with unknown causes present in the globe. To find out such unknown effects of drugs and unknown causes of diseases research study designs, pharmacoepidemiological studies are useful. The sequence of level of evidence and studies include Meta analysis, RCT (randomized control trail), Non RCT, cohort study, case - control study, cross sectional study, case report. Meta analysis and RCT gives accurate information when compared with other studies as given in sequence in the above. [2] With the help of research study designs investigators must generate some data regarding drugs effects, diseases etiology and perform the interventions pertaining to study. So the investigator should elect suitable study design to find an answer to the question. As we know that investigators and researcher are health detectors, their ultimate goal is providing better patient care. [4, 5] So, especially the researcher should focus on pediatrics and geriatrics why because they often excluded from the clinical trials, thus strange effects will be arising to the special population. [6, 7] To attain better results the researcher must separate out the study into five steps planning, performance, documentation, analysis and publication. At the final stage difficulties may arise to minimize the errors. The well designed study can minimize 1Sri Padmavathi School of Pharmacy, Tiruchanoor, Tirupati-517503, Andhra Pradesh, India. E-mail: bvinaypradeep@gmail.com *Corresponding author 2SV Medical College, Tirupati-517501, Andhra Pradesh, India. errors. [8] The main aim of this review of literature is simplifying the concepts and providing brief an idea on research study designs. Types of Designs Research study designs are classified into two types as follows: 1. Observational Designs In observational study the subjects or recruited population are just observed, as name indicates no interventions are taken place. [5] Based on the time, observational study designs are further categorized into analytical study and descriptive study (Figure 2). And main goal of the various study designs include Descriptive study is to generate hypothesis, Analytical study is to test hypothesis and Experimental study is to prove hypothesis. [4, 9] a. Analytical I. Cohort Cohort means group of warriors, group of soldiers marching together as per Latin word cohor and roman literature. [4, 5] Cohort study is also named as: Follow up study (prospective study), [4, 5, 9, 10] Forward looking study, [9] Incidence study, [4, 5, 10] Longitudinal study. [4, 5,11] A cohort study is a study, starts with exposure (risk factor) and follow for the outcome (disease). That means the study consists two group s first group is exposed to some risk factor and second group free from exposure (Figure 3). Then follow the each group to find out the disease status. Compare the disease risk between exposed group and unexposed group. For example, a group of smokers and a group of non smokers, follow the two groups for the outcome (lung cancer). Cohort study can assess the cause, natural history of the disease, relative risks (RR) and incidence rate. The study Disadvantages include greatest cost, longer time, susceptible to selection bias, loss of follow up (attrition). [9] Cohort study can measure risk (it is the probability of developing an outcome when exposed to a drug) it is calculated by the relative risk (RR), incidence (absolute risk) and risk difference (attributable risk). [2, 12, 13] 1
REVIEW ARTICLE Research Studies Observational Studies (The Does not Involve Any Intervention) Analytical Experimental Studies (The Involves Intervention) Descriptive Randomized Non-randomized Figure 1: kinds of research study design Observational Studies Analytical Studies (Comparison Group Present) Cohort Studies Casecontrol Descriptive Studies (No Comparison Group) Crosssectional Case Report Case Series Surveys Figure 2: observational study designs Disease Exposed No Disease Populaton Disease Non-exposed No Disease Exposure Follow Up Out Come Figure 3: Schematic design of cohort study Case-control study is a retrospective study that means opposite to cohort study/mirror image of cohort study, the study start with outcome and search for the risk factor by taking case records. [2] This study includes case group (people with diseases) and control group (people without disease) as a comparison. The study initiates with outcome and look backwards to identify the exposure (risk factor) by history of cases taken from the medical records (Figure 4) and it is also performed through the conducting the interviews. [14] Case-control study is also named as: Historical study, [4] Backward looking, [9] Retrospective/Retrolective study, [5, 10] Longitudinal study, [11] Case-reference study. [10] For example, the cases with peptic ulcers and controls without peptic ulcers and looks back there history whether they exposed to NSAIDS or not. The case-control studies are widely used to assess the safety of drugs. Compare to the Outcome of exposed to a drug Relative risk = Outcome of unexposed group to a drug Incidence Number of new cases during specified period = Total presons was observed in specified period Risk difference = outcome of exposed group outcome of non-exposed group Retrospective cohort (Historical, Non-Concurrent) is another kind of study, the investigator select old patients from the case records or registry and he observes them for outcome. The direction of observation is always forwards in cohort studies. [4, 5] II. Case-control 2
REVIEW ARTICLE Cases People With Disease Controls People Without Diesease Case History/ Registry Exposure Backward Look Out Come Figure 4: Schematic design of case-control study Past Present Future Cross-Sectional Prospective Cohort Retrospective Case-Control Randomized Control Time Figure 5: Time relationship of different studies population. So it is ideally apt to measure the prevalence. [9, 12] Cross sectional study also named as: Prevalence study, [4, 5, 13] Instantaneous study, [4, 13] Simultaneous study, [4, 13] Snap shot study, [13, 14] Transversal study. [15] Cross sectional studies are conducted through surveys, database analysis or medication chart reviews. Census is the perfect example for cross sectional study. [4, 13] Advantages include data available readily, good for assessing the prevalence, follow up not necessary, fast and inexpensive. And disadvantages include not suitable for acute disease, no comparison group, susceptible to bias and causality cannot be determined. [4, 5, 14] Prevalence calculated by the following two formulae as below: [3] cohort study, case-control studies are easy to conduct and takes less time and lesser cost. Disadvantages include susceptible to bias (selection bias and information bias), case-control study not appropriate when the outcome is not unknown. [9] Odd ratio is the risk estimator in casecontrol study. It can also used in randomized control trails, cohort studies to estimate risk. Odd ratio is calculated using the formula as below. [12, 13] Odd ratio = a c ad = b d bc Where, a = number of persons exposed and with disease, b = number of persons exposed but without disease, c = number of persons unexposed but with disease, d = number of persons unexposed and without disease, a, c = total number of persons with disease (cases), b, d = total number of persons without disease (controls). point prevalence = Cases during a given specified point of time 100 total population during the period Period prevalence = cases during a given time period 100 total population during the same time period III. Cross Sectional Cross sectional study is a study in that measures exposure and outcome at the same time in randomly selected population, that means ask the questions and get the answers regarding exposure and outcome (determines presence or absence of exposure and presence or absence of disease outcome for each individual), follow up is not necessary for this study (no time sense, people examine only one point of time). Cross-sectional study is useful to assess presence (prevalence) of disease in the selected Different Analytical Observational Hybrid Designs Nested Case-control and Case-cohort : Nested casecontrol study or case-control in cohort study means cases and control groups are elected from the cohort study. That means which are developed diseases as cases and which 3
not developed diseases are as controls will be taken from case control study. Nested case-cohort is also same as the nested case-control study. But, in this study cohort is taken randomly as a control and as a comparison. Cases may present in cohort to be analyzed. [4, 5] b. Descriptive I. Case Report Case report is usually reports of events and individual patient experience on drug exposure and outcome observed in the single patient. Case reports are useful to set hypothesis for causation of an event. So it gives alarming signal for other health care professionals on the event. [3] But case report should be details of a rare disease, abnormal drug reaction and ADRs. This rare events are have been collected by the WHO, Uppsala monitoring center. [16] For example, case report on Thalidomide that causes to human Teratogenicity, later helped in to confirm that could produce fetal abnormalities. The case report of Hypertricosis with the use of Minoxidil for hypertension also helped in developing Minoxidil as a topical preparation for baldness. [13] II. Case Series Case series are collection of case reports (multiple patients with the same findings), who have a similar single exposure or similar outcomes later the treatment; it may be based on either exposure or outcome. Event, happened in the patients is confirmed by the more case reports availability that means case reports of common events, stronger will be the confirmation. Case series are mainly useful to find out the ADRS. It is also named as open trail. [17] III. Surveys The term survey means the collection of information from a group. The types of information include Demographics, Attitudes, Opinions, Knowledge and Behaviors. The population may be patients, learners, researchers and colleagues. And this survey goes between surveyors and respondent, it may be done through face to face, telephone or with no personal interaction that means through the postal, fax, web survey. The collection of information is through asking questions that is why questionnaires must be well designed. There are several steps involved in conduct the survey as follows: Frame the research question Develop the survey Pilot text of the survey (a small survey in the targeted population helps in the researcher to frame the questions, modifications or removal in questions. This is done before commencing the study.) [18] IV. Ecological Ecological study is one kind of descriptive study. Ecological study is also named as Correlation, Analysis of Secular Trends and Aggregated Data. It is based on existing statistical data is compared with the prevalence and incidence of diseases in the populations or country. This study is also useful to compare the data region to region and country to country. For example, New Zealand mortality increased with anti-asthmatic drug use, using statistical data of country. So, with that they can identify incidence and prevalence in the country. This study is depended on individual data if not available it leads the bias, called as ecological fallacy or aggregation bias. [1, 5, 13, 19] Biases in Observational Studies Bias or errors in the study causes the results inaccurate. The different biases include, 1. Confounding Bias Confounder is an additional risk factor or variable related with exposure/disease that affects the outcome (other than the risk factor). For example, alcohol and smoking; people who drink alcohol lead to the cancer. We know that smoking is also cause cancer. Some people drink alcohol at the same time smoking too. Thus, smoking is the confounder between the alcohol and cancer. [10, 11, 13] 2. Selection Bias Selection bias is a problem in observational studies why because in which groups are not randomization. Groups assigned as their wish. If groups are not balanced based on the characteristics, we get irregular and unbalanced groups, ultimately it effects on results. [10, 11, 13] 3. Information Bias The inaccurate information collected from subjects, results in giving the wrong outcome. This inaccurate information may come from the either subjects or personnel. [10] 4. Protopathic Bias The electing of a diseased person but not recognized during commencing the study, disease may appear after the drug intake cause to misleading of the study. For example, gastric carcinoma and anti-ulcer drug Cimetidine. Actually the Cimetidine, it is not causes to the gastric carcinoma. [13] 5. Measurement Bias If many groups are involved in the study, the personnel measuring, instruments used are the two major problems to arise this bias. [13] Bias Controlling 1. Matching/ Stratification/ Restriction Matching, stratification (Strata means groups or blocks) and restriction (Allowing the same age group subjects to the study) are the strategies to control the bias. Bias controls by the matching the patient groups and the control groups with respect to the base line characteristics (age, sex, etc...). For example, if we take 54 years old cirrhosis patients, as the same way we should take 54 years old normal subjects as a control group. If we take 40 50 years old patients they should compare with 40 50 years old controls. Age is a common confounder in these studies. [10, 11] 4
Experimental Studies Randomized (Partcipants Randomly Allotted) Non-randomized (No Randomization) Controlled (Control Group In The ) Uncontrolled (No Control Group) Controlled Uncontrolled Parallel Cross Over Figure 6: Experimental study designs Randomized Population Interventonl Group Regular Follow Up Out Comes Measured Control Group Regular Follow Up Out Comes Measured Figure 7: Schematic diagram of randomized controlled study 2. Experimental (Interventional ) Experimental studies are not as the observational studies there is an intervention taken place. Thus, it is also named as interventional study. The national institute of health (NIH) defined an interventional study as individual in which participants receive specific interventions according to the research plan created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or changes to participants behavior. [14] Experimental study designs further classified as follows based on the randomization. The Concept and Importance of Randomization Randomization is the core of the experimental study and it means randomly electing of eligible individuals from a population. Randomization done by the tossing of coin, random number tables, computer generated numbers. Tossing a coin gives 50:50 chances. Random number table is a good technique and for that alternative is computer generated numbers, bias is not involved in these studies because of randomization. [9] However, randomization should done by the pharmacist, if others involved like researchers it will lead to influence on trail and bias, finally the results are unreliable. [20] a. Randomized I. Randomized Controlled Randomized control study design is the highly reliable design and it is high level evidence to practice health profession. [14] As name indicates, control group is present as a comparator to the interventional group. In this study interventional group receives interventional drug and control group receive either old drug or placebo (Figure 7). For randomized controlled study is also named as: Clinical trail Gold standard study. Why Use Controls and the Concept Placebo as Control? The comparison must be needed between new Interventional drugs and older drugs, then only we know which one is better and safe for the patients, otherwise we cannot say which is safe to treat. [9] And placebo should use as a control if no drug present to treat a disease. Placebo is an inactive medication having no pharmacological action, but sometimes person may feel better due to the psychological effect of receiving some medication. [9] Randomized study further divided into two types, one is parallel design (Figure 8) and another one is cross-over design (Figure 9). It is classified based on the treatment receiving of two groups. The parallel study is a simplest study and widely used study. In this study interventional group receive interventional drug and control group receive old drug or Placebo throughout the study. [10, 11] But, in cross-over study both groups receive both drugs. How means, until the washout period or cooling period interventional group receive interventional drug and control group receive old drug or placebo, after the washout period the treatments are exchanged then interventional group receive old drug or placebo and control group receive interventional drug, that means interventional group becomes control group and control group becomes interventional group. [5, 9, 11] 5
Randomized study population Interventional Group Interventional Drug (New drug) Out Comes Measured Control Group Placebo/ Old Drug Out Comes Measured Figure 8: Parallel study design Randomized Population Interventional Group Control Group Interventional Drug Placebo/ Old Drug Out Comes Measured Out Comes Measured Wash Out Period Wash Out Period Placebo/ Old Drug Interventional Drug Out Comes Measured Out Comes Measured Figure 9: Cross over deign Non-randomized Population Interventonl Group Regular Follow Up Out Comes Measured Control Group Regular Follow Up Out Comes Measured Figure 10: Non-randomized controlled study Blinding assist in bias elimination in the study participants, follow up examiners, treatment administrators, ancillary staff involved in the study. It can be prevented at different levels by hiding or blinding or masking. Blinding is three types based upon the persons blinding in the study. Single blinding ( patient alone) Double blinding (patient and clinician) Triple blinding (patient, clinician and statistician) Without the blinding accurate results are not obtained. Extra concentration of Clinicians, treatment administrators and other personnel may possible on particularly some patients who are receiving interventional drug. Blinding process revealed after the entire study completed. Unblinding may also do when benefit or harm is revealed in groups. [9] II. Randomized Uncontrolled In this study there is no control group present only one group present with randomization. It is so weaker when this study compared with the randomized control study. b. Non - randomized I. Non - randomized Controlled The study is same as that of the randomized control study but without randomization. The control group receive placebo or old drug and interventional group receive interventional drug finally outcomes measured (Figure 10). Sometimes hospital records data obtained from published literature can be used as a control group, such nonrandomized or non-current studies named as historical control studies. II. Non - randomized Uncontrolled This study is also same as that of randomized uncontrolled study but without randomization and control group. Outcomes measured finally after the collection. Different Randomized and Non-Randomized Trails 1. Cluster Randomized Cluster means group and this study itself consists subjects as randomization. The study goes on group wise, not on the basis of individuals. Examples for group includes - Schools in a city, Villages, Religion, Ethnicity and Occupation wise in an area. This is the simple to randomize the participants by groups than individual. Even the results are done by group not by individuals. [4, 5] 2. Latin Square Design Latin square design helpful to study more than the one treatment simultaneously to understand the usefulness of each treatment by the comparison. For example, four treatments namely A, B, C, D. then Latin square is applied (four replications of each treatment) as follows and do comparison. [10] A B C D B C D A C D A B D A B C 3. Factorial Randomized In this study, only one control group and two interventional groups are present. The results of each group comparing with the control group. And with the help of this study we 6
can assess at a time two factors (treatment and dosage form). [9, 10] 4. Multi Centric Trails Research goes at a time in many centers by sponsored organization. They collect the data from the each group, combined as a single study and evaluated. All the data pertaining to the study should sent to the sponsored organization periodically, finally they done publication. Individual center has no rights to publish data independently at the any phase. [9] 5. Field Trails (Field ) Field trails are an Interventional studies and field means other than the clinics. In this trails disease free population elected to aware and reduce the risk of development of disease in the field. Field trails are of two types. [21] a. Individual level b. Aggregated level (community trails) The trail done in communities (School, house hold, community), thus they are named as community trails. Especially the trails are being conducted with regarding to the disease. The selection of disease is based on the researcher interest. In community, awareness camp goes first; each people were interviewed and analyzed before conducting the study. After the one or two years later, their knowledge and behavior were assessed regarding the life style modification as well as blood pressure, weight, plasma cholesterol measured. Face to face interaction, direct counseling regarding disease and regarding life style modification are advantages of this study; result in the decrease in the risk development of diseases and control of some chronic diseases in community. [10, 21] 6. Therapeutic Trails and Prophylactic Trails Therapeutic trails nothing but the randomized control trails in which interventional group receives interventional drug and control group receives either old drug or placebo. Finally, they compare the each drug for effectiveness as well as related to healing of the disease. Prophylactic trails are same as therapeutic trails. Two groups are taken one as prophylactic group (protected group) and another one as control (unprotected group). Prophylactic group is treated with prophylactic treatment and control is not. These two groups are observed and results should be protected group may cured from particular disease than the unprotected group. [10] 7. Quasi Experimental Design Researchers do research sometimes on intact groups (the groups are already formed rather than the random selection). The groups are not electing randomly from the larger population, so it leads to wrong results at the final step and this is problem faced by the researchers during conducting the study, but need to do the research. So, it is described as quasi-experimental study design. Quasiexperimental design categorized into two types. [5] a. Time design b. Non-equivalent control group design Time design, the study goes without control group and requires only one experimental group. The variable is measured on experimental group by giving the experimental treatment. So, due to the lack of control group we cannot identify whether the experimental treatment superior or not when compared with the existing drug. Statistical comparison or mean is done through following the treatment group on the same variable. In Nonequivalent control group design the study goes with control group. Both groups are intact groups and they pre-tested and post-tested and finally made conclusions through the data collected. Assumption of equivalence regarding the study cannot be made between the groups (significant difference) and it is possible when pre-tested. If null hypothesis is acceptable, then the researcher can begin his experiment on the assumption that he has equivalent groups. Some may suggest analysis of covariance (statistical analysis) rather than the experiment. [5] PHARMACOEPIDEMIOLOGY IN INDIA Pharmacoepidemiology came to India in late seventies, but still there is no drastic improvement in research studies. Indian researchers are interested to do mostly in conducting drug utilization studies and these studies are useful to generate hypothesis, whereas no one is interested in interventional studies. In India studies are - classes of prescribing drugs, the number of drugs per prescription, the number of fixed dose drug formulation, injectable and so on and there is no further step in studies even on drug utilization studies. Studies are not running even by using internationally accepted measures such as daily defined doses (DDD) is not done. It was showing that lack of knowledge, laziness, apathy and unwillingness to conduct the better study. Ultimately saying that Indians are restricting themselves to observational studies and to see Indians are not interested to do the interventional studies. [22] CONCLUSION The drugs are approved by performing trials within the limited people and within short time. Thus, drugs after enter into the market, it become use vastly in the different population and chances for arising the drug related problems. The better way is to minimize drug related problems, research study designs or pharmacoepidemiological studies going to be helpful and the Pharmacists as a health care professional play a key role in scientific progress regarding the safety profile of drugs (unknown and unsuspected drug effects), disease. And generation of hypothesis is not enough, interventions are needed. So problems arise during usage of drugs by patients should detect and analyze the problem by performing appropriate study design and ultimately help in patient care. REFERENCES 1. Bernard Begaud. Dictionary of epidemiology. Published by John Wiley & Sons Ltd, UK, 2000. 7
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