Clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s are medical research studies conducted on human subjects. The human subjects are assigned to one or more interventions, and the investigators evaluate the effects of those interventions. The progress and results of clinical trials are analyzed statistically.

Analysis factors

Intention to treat

Randomized clinical trials A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...

analyzed by the intention-to-treat (ITT) approach provide fair comparisons among the treatment groups because it avoids the

bias Bias is a disproportionate weight ''in favor of'' or ''against'' an idea or thing, usually in a way that is closed-minded, prejudicial, or unfair. Biases can be innate or learned. People may develop biases for or against an individual, a group, ...

associated with the non-random loss of the participants. The basic ITT principle is that participants in the trials should be analysed in the groups to which they were randomized, regardless of whether they received or adhered to the allocated intervention. However, medical investigators often have difficulties in accepting ITT analysis because of clinical trial issues like missing data or adherence to

protocol Protocol may refer to: Sociology and politics * Protocol (politics), a formal agreement between nation states * Protocol (diplomacy), the etiquette of diplomacy and affairs of state * Etiquette, a code of personal behavior Science and technology ...

Per protocol

This analysis can be restricted to only the participants who fulfill the protocol in terms of the eligibility, adherence to the intervention, and outcome assessment. This analysis is known as an "on-treatment" or "per protocol" analysis. A per-protocol analysis represents a "best-case scenario" to reveal the effect of the drug being studied. However, by restricting the analysis to a selected patient population, it does not show all effects of the new drug. Further, adherence to treatment may be affected by other factors that influence the outcome. Accordingly, per-protocol effects are at risk of bias, whereas the intent-to-treat estimate is not.

Handling missing data

Last observation carried forward

One method of handling missing data is simply to impute, or fill in, values based on existing data. A standard method to do this is the Last-Observation-Carried-Forward (LOCF) method. The LOCF method allows for the analysis of the data. However, recent research shows that this method gives a biased estimate of the treatment effect and underestimates the variability of the estimated result. As an example, assume that there are 8 weekly assessments after the baseline observation. If a patient drops out of the study after the third week, then this value is "carried forward" and assumed to be his or her score for the 5 missing data points. The assumption is that the patients improve gradually from the start of the study until the end, so that carrying forward an intermediate value is a conservative estimate of how well the person would have done had he or she remained in the study. The advantages to the LOCF approach are that: * It minimises the number of the subjects who are eliminated from the analysis, and * It allows the analysis to examine the trends over time, rather than focusing simply on the endpoint. However, the

National Academy of Sciences The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...

, in an advisory report to the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

on missing data in clinical trials, recommended against the uncritical use of methods like LOCF, stating that "Single imputation methods like last observation carried forward and baseline observation carried forward should not be used as the primary approach to the treatment of missing data unless the assumptions that underlie them are scientifically justified."

Multiple imputation methods

The National Academy of Sciences advisory panel instead recommended methods that provide valid

type I error In statistical hypothesis testing, a type I error is the mistaken rejection of an actually true null hypothesis (also known as a "false positive" finding or conclusion; example: "an innocent person is convicted"), while a type II error is the fa ...

rates under explicitly stated assumptions taking missing data status into account, and the use of multiple imputation methods based on all the data available in the model. It recommended more widespread use of Bootstrap and

Generalized estimating equation In statistics, a generalized estimating equation (GEE) is used to estimate the parameters of a generalized linear model with a possible unmeasured correlation between observations from different timepoints. Although some believe that Generalized es ...

methods whenever the assumptions underlying them, such as

Missing at Random In statistics, missing data, or missing values, occur when no data value is stored for the variable in an observation. Missing data are a common occurrence and can have a significant effect on the conclusions that can be drawn from the data. Mi ...

for GEE methods, can be justified. It advised collecting auxiliary data believed to be associated with dropouts to provide more robust and reliable models, collecting information about reason for drop-out; and, if possible, following up on drop-outs and obtaining efficacy outcome data. Finally, it recommended sensitivity analyses as part of clinical trial reporting to assess the sensitivity of the results to the assumptions about the missing data mechanism. While the methods recommended by the National Academy of Science report are more recently developed, more

robust Robustness is the property of being strong and healthy in constitution. When it is transposed into a system, it refers to the ability of tolerating perturbations that might affect the system’s functional body. In the same line ''robustness'' ca ...

, and will work under a wider variety of conditions than single-imputation methods like LOCF, no known method for handling missing data is valid under all conditions. As the 1998 International Conference on Harmonization E9 Guidance on Statisticial Principles for Clinical Trials noted, "Unfortunately, no universally applicable methods of handling missing values can be recommended."International Conference on Harmonization, Guidance for Industry E9, Statistical Principles for Clinical Trials
1998 Expert statistical and medical judgment must select the method most appropriate to the particularly trial conditions of the available imperfect techniques, depending on the particular trial's goals, endpoints, statistical methods, and context.