Non randomized controlled trial
- 1. PRESENTED BY :- HIMIKA RATHI MPHARM-DEPARTMENT OF PHARMACOLOGY L.M COLLEGE OF PHARMACY
- 2. CONTENT Taxonomy of study designs to assess the effectiveness of an intervention Definition of a Non-Randomized Trial Introduction Sources of bias in nonrandomised studies Commonly used methods of statistical adjustment When is it appropriate to use a non-randomized trial design? Disadvantages of the Nonrandomized Clinical Trial Similarities between RCT and NON RCT Differences between RCT and NON RCT Summary
- 3. • Experimental designs • A study in which the investigator has control over at least some study conditions, particularly decisions concerning the allocation of participants to different intervention groups. • 1. Randomised controlled trial • Participants are randomly allocated to intervention or control groups and followed up over time to assess any differences in outcome rates. Randomisation with allocation concealment ensures that on average known and unknown determinants of outcome are evenly distributed between groups.
- 4. • 2. Quasi-randomised trial • Participants are , but the method of allocation falls short of genuine randomisation and allocation concealment (e.g. • 3.Non-randomised trial/quasi-experimental study • The investigator has control over the allocation of participants to groups, but Differs from a ‘cohort study’ in that the intention is experimental rather than observational.
- 5. • Observational designs:- • A study in which natural variation in interventions (or exposure) among study participants is investigated • 4. Controlled before-and-after study of participants who have received an intervention and those who have not, It can also be considered an experimental design if the investigator has control over, or can deliberately manipulate, the introduction of the intervention.
- 6. Observational designs • 5. Concurrent cohort study • A follow-up study that compares outcomes between participants who have received an intervention and those who have not • 6. Historical cohort study • A variation on the traditional cohort study where the , i.e. participants are not studied concurrently.
- 7. • 7. Case–control study • Participants with and without a given outcome are identified (cases and controls respectively) and exposure to a given intervention(s) between the two groups compared. • 8. Before-and-after study • Comparison of outcomes from study participants before and after an intervention is introduced. The before and after measurements may be made in the same participants, or in different samples. It can also be considered an experimental design if the investigator has control over, or can deliberately manipulate, the introduction of the intervention
- 8. • 9. Cross-sectional study • Examination of the • 10. Case series • Description of a number of cases of an intervention and outcome (no comparison with a control group).
- 10. Definition of a Non- Randomized Trial A study where participants have been assigned to the treatment, procedure, or intervention alternatives by a method that is not random. The investigator defines and manages the alternatives. A clinical trial in which the participants are not assigned by chance to different treatment groups. Participants may choose which group they want to be in, or they may be assigned to the groups by researchers.
- 11. INTRODUCTION The ultimate goal of the evaluation of healthcare interventions is to produce a valid estimate of effectiveness, in terms of both internal and external validity. Internal validity concerns the extent to which the results of a study can be reliably attributed to the intervention under evaluation, whereas external validity concerns the extent to which a study’s results can be generalised beyond the given study context. The randomised controlled trial (RCT) is widely regarded as the design of choice for the assessment of the effectiveness of healthcare interventions.
- 12. The main benefit of the RCT is the use of a randomisation procedure that, when properly implemented, ensures that the allocation of any participant to one treatment or another cannot be predicted. RCTs are also more likely to employ specific measures to reduce or remove bias, such as blinded outcome assessment. several scenarios remain under which an RCT may be unnecessary, inappropriate, impossible or inadequate. Examples include the assessment of rare side-effects of treatments, some preventive interventions and policy changes
- 13. Sources of bias in nonrandomised studies In non-randomised studies, selection bias will be introduced when participants chosen for one intervention have different characteristics from those allocated to the alternative intervention (or not treated). The choice of an intervention under these circumstances will be influenced not only by a clinician’s own personal preference for one intervention over another but also by patient preference, patient characteristics and clinical history. when faced with a patient who may be eligible to receive a given intervention, the decision to treat will be influenced by some factor that in turn is related to the treatment outcome. This introduces systematic bias leading to either over- or underestimates of treatment effects, depending on the treatment decision mechanism.
- 14. Non-randomised studies are also susceptible to attrition, detection and performance bias. For example, attrition bias will occur if there are dropouts, detection bias if the assessment of outcomes is not standardised and blinded, and performance bias if there are errors and inconsistencies in the allocation, application and recording of interventions. The traditional solution to removing selection bias in non-randomised studies has been to attempt to control for known prognostic factors, either by design and/or by analysis. Alternative statistical techniques for removing bias in non- randomised studies are also present.
- 15. Commonly used methods of statistical adjustment Standardisation:- Participants are analysed in groups (strata) which have similar characteristics, the overall effect being estimated by averaging the effects seen in each of the groups. Propensity scores :- Propensity probabilities are calculated for each participant from the data set, estimating their chance of receiving treatment according to their characteristics. Treatment effects are estimated either by comparing groups that have similar propensity scores (using matching or stratification methods), or by calculating a regression adjustment based on the difference in average propensity score between the groups.
- 16. When is it appropriate to use a non- randomized trial design? The first is when an RCT would be ideal but practical considerations (e.g., costs, unacceptability to patients or providers) make a high-quality RCT infeasible. When the act of random allocation may reduce the effectiveness of the intervention –Occurs when the effectiveness of the intervention depends on the participant’s active participation which is influenced by their beliefs and preferences) When there are legal or political obstacles to random allocation
- 17. Define Inclusion/Exclusion Criteria Specific inclusion and exclusion criteria need to be established for the study population. Inclusion criteria must be identical for both the intervention and comparison groups. There is an inherent tension between using criteria that are broad enough to ensure that recruitment of an adequate sample and generalizability, but not so broad that meaningful comparison is not possible. Exclusion criteria have two main purposes: (1) to exclude study subjects who present substantial risk to the scientific quality of the study (e.g., inability to follow up, plan to move out of state)
- 18. • (2) to assure safe and ethical conduct of the study (e.g., inability to tolerate general anaesthesia , contraindications to the one or both of the treatment arms, unable to give informed consent) Both clinical characteristics of potential study subjects and social/cognitive criteria should be considered when identifying exclusion criteria.
- 19. Allocate Subjects Between Groups The selection of study sites and the allocation of subjects to treatment groups are among the most challenging issues in nonrandomly assigned control group studies. For example, the investigator may choose to randomly select one of two comparable private hospitals as the intervention site and the other as the comparison site. Whether to randomize by hospital, ward or clinic, or physician will depend on feasibility, risk of contamination, and the nature of the intervention. The use of patient or physician preference to allocate patients to treatments can be used
- 20. Collect Baseline Data In the nonrandomized controlled trial, it is crucial to collect a comprehensive dataset including all variables that can reasonably be expected to influence the outcome of the procedure. Baseline and follow-up (i.e., pre/post) measures should be collected at both the intervention site and the control sites. This data will allow the investigator to judge the comparability of the two groups and can also be used to statistically adjust for measured differences between the groups.
- 21. Measure the Outcome The outcome of interest should be established before initiating the study and measured as accurately and reliably as possible. Because neither the patient nor the investigator is blinded to the nature of the procedure, the use of physician- and patient-reported outcomes can be quite problematic. The use of independent, blinded evaluators, imaging studies, or physiologic measurements (e.g., blood flow rate, degree, residual stenosis) may be less prone to bias than patient- reported outcomes.
- 22. REASONS FOR THE USE OF NONRANDOMIZED STUDIES 1. Nonrandomized studies are sometimes the only ethical way to conduct an investigation. If the treatment is potentially harmful, it is generally unethical for an investigator to assign people to this treatment. An example of this is a study of the effects of malnutrition, where we simply cannot assign subjects to intolerable diets. Thus we compare malnourished populations with those on adequate diets. 2. Nonrandomized studies are sometimes the only ones possible. Certain investigations require the implementation of treatments that may affect people's lives.
- 23. REASONS FOR THE USE OF NON RANDOMIZE D STUDIES 3. Nonrandomized studies are usually less expensive. An advantage of nonrandomized studies is that they usually cost less per subject and may not require the extensive planning and control that are needed for randomized studies. This makes nonrandomized studies particularly attractive in the early stages of any research effort 4.The use of a nonrandomized control group may also reduce the threats to external validity that limit the value of RCTs results. First, RCTs tend to be done at a few, highly selected sites, and are rarely done in community settings. Quasi-experimental designs can often involve more providers and settings, making the results more generalizable.Second, the lack of randomization often facilitates recruitment of a larger proportion of eligible patients, thus further increasing generalizability.
- 24. Disadvantages of the Nonrandomized Clinical Trial The principal disadvantage of this design is the potential for bias from confounding. The direction of this bias is unpredictable from study to study. For example, clinicians may differentially include the sicker patients in the intervention trial to provide the “best chance” for the patient, thus biasing the trial against the intervention. Alternatively, the healthiest patients may be included to ensure that the intervention has the optimal opportunity to work. Therefore, the investigator should try to pre-empt “hand-picking” study subjects who receive the intervention.
- 25. Disadvantages of the Nonrandomized Clinical Trial Even when optimally conducted, this design can never ensure that unmeasured or imprecisely measured social, economic, cultural, or clinical variables do not account for the apparent treatment effect. Thus the results of these trials must be evaluated in a larger context, and internal and external validity may be best assessed through the replication of results in a variety of clinical settings.
- 26. Similarities between RCT and NON RCT These are both experimental study designs. Study participants in both studies are subjected to some type of treatment/ intervention and control group. Some outcome of interest is measured. The researchers test whether differences in this outcome are related to the treatment/ intervention or not.
- 28. Differences between RCT and NON RCT RANDOMIZED CONTROLLED TRIAL 1. RCT is an experimental study design where the subjects in a population are randomly allocated to different groups. 2. Also known as randomized study. 3. Study population are selected randomly. 4. Randomization is the main ingredient of RCT. NON RANDOMIZED CONTROLLED TRIAL 1. NON RCT is an experimental study design where the subjects in a population are non randomly allocated to different groups. 2. Also known as Quasi experimental design. 3. Study population are chosen 4. Randomization is not the main ingredient of NON RCT
- 29. RANDOMIZED CONTROLLED TRIAL 5. Have high scientific validity. 6. It provides the best scientific evidence to any study. 7. It is considered as an ideal design for evaluating both the effectiveness and side effects of interventions. 8. RCT can be used up to a point unless there is any real world constraint for random assignment. NON RANDOMIZED CONTROLLED TRIAL 5. It has moderate scientific validity. 6. Evidences generated from this design are relatively of low significance while compared to RCT. 7. It is not considered as an ideal design for evaluating both the effectiveness and side effects of interventions. 8. NON RCT is used real world constraints like ethical, political or logistical constraints do not allow for randomization
- 30. RANDOMIZED CONTROLLED TRIAL 9. It has less potential for bias, or confounding and study validity is not compromised. 10. RCTs cannot be conducted and are not realistic at all times due to some practical or ethical reasons. Example:- while conducting studies related to exposure of harmful chemicals, we cannot randomized people to receive the harmful chemicals. 11. These are generally quite expensive. NON RANDOMIZED CONTROLLED TRIAL 9. It has relatively increased potential for bias, or confounding and study validity is compromised. 10. It can be conducted without violating ethical considerations. 11. These are generally less expensive.
- 31. SUMMARY • Uses natural groups or assigns participants to groups using a non-random procedure. • While nonrandomized studies are cheaper, more easily carried out, and can be done retrospectively, inferences from them are generally more suspect than are those from randomized studies. • But even when optimally conducted, this design can never ensure that unmeasured or imprecisely measured social, economic, cultural, or clinical variables do not account for the apparent treatment effect.
- 33. REFERENCES • http://archpedi.ama-assn.org/cgi/content/full/161/5/495 • Nonrandomized Interventional Study Designs (Quasi-Experimental Designs) David A. Axelrod, MD, MBA and Rodney Hayward, MD • Evaluating non-randomised intervention studies BY JJ Deeks and J Dinnes • https://doi.org/10.1136/bmj.g4115