Define prospective randomized controlled trial

A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Many valuable case-control studies, such as Lane and Claypon's investigation of risk factors for breast cancer, were retrospective investigations.

Most sources of error due to confounding and bias are more common in retrospective studies than in prospective studies. For this reason, retrospective investigations are often criticised. If the outcome of interest is uncommon, however, the size of prospective investigation required to estimate relative risk is often too large to be feasible.

In retrospective studies the odds ratio provides an estimate of relative risk. You should take special care to avoid sources of bias and confounding in retrospective studies. Prospective investigation is required to make precise estimates of either the incidence of an outcome or the relative risk of an outcome based on exposure. Twelve patients Patients who were cured were younger Patients enrolled in PRTs were more likely to be cured We performed a logistic regression analysis entering the independent variables of age, male gender, admission APACHE II score, evidence of antimicrobial resistance, and PRT enrollment as risk factors against the binary outcome of cure or failure.

Exclusion criteria for the 46 patients not enrolled in PRTs also were reviewed Table 8. All patients who had evidence of an allergy to antibiotics were allergic to penicillins or the specific agents under study. Ten patients had no evidence of a specific exclusion criterion that would have prevented enrollment into a PRT. Patients in whom treatment failed had a higher incidence of antibiotic resistance Five patients Patients not enrolled in PRTs had a higher incidence of yeast recovered on culture, but this was not statistically significant.

There was no significant correlation between species recovered from initial culture and cure. Polymicrobial infections were more common among patients enrolled in PRTs Fourteen patients Patients not enrolled in PRTs had a higher incidence of resistance to antibiotics These patients required more days of intravenous antibiotic therapy Forty-seven patients Patients with an abscess were more likely to be cured than those with generalized peritonitis Sixty-eight episodes of extraabdominal infections occurred in 44 patients.

Patients not enrolled in PRTs were more likely to have extraabdominal infections The development of an extraabdominal infection was associated with a lower rate of cure Patients requiring ICU care were less likely to be cured At our institution, patients with intraabdominal infections who were enrolled in a PRT had better outcomes than those who were excluded or not entered into a clinical trial.

Increasing age 7,8,10,13—21 and higher APACHE II scores 7,10,14,17,19—21 have previously been shown to be independent predictors of treatment failure and death for patients with intraabdominal infections. In the current study, patients older than 50 years and those with APACHE II scores greater than eight had significantly higher rates of treatment failure, a finding observed in both the PRT and not-enrolled groups.

Concomitant illness has been reported to be a significant risk factor for treatment failure in other studies evaluating intraabdominal infection. Trial eligibility criteria restricted the participation of patients with comorbid diseases that have been reported to increase the death rate of patients with intraabdominal infections.

Excluding sicker patients from trial participation based on rigid eligibility criteria may have had the unintended effect of creating two heterogeneous groups of patients. The group not enrolled in PRTs may have been less likely to be cured because of factors imposed by concomitant illnesses that limited their physiologic reserve. In contrast, patients who meet eligibility criteria and therefore can be enrolled in PRTs are healthier overall, have fewer comorbid diseases, and are more likely to be cured of infection.

The source of intraabdominal infection has been shown to be another important determinant of outcomes. Patients with complicated appendicitis have repeatedly been shown to have a lower death rate and fewer complications than patients with other causes for intraabdominal infection.

Postoperative infections have been associated with higher death rates than many other sources of intraabdominal infection. Although there are multiple factors that affect cure and survival in intraabdominal infections, the importance of risk stratification, especially by source of infection, cannot be overemphasized. Intraabdominal abscesses were more common among patients with postoperative infection.

Previous reports have shown that patients with a localized infection have better outcomes than those with generalized peritonitis. The beneficial effect that enrollment in a clinical trial can have on outcomes is not new. One theory suggests that patients enrolled in clinical trials receive better medical care. Patient motivation has been speculated to improve outcomes in cancer chemotherapy trials. In our experience, the overall desire of patients to participate in PRTs is high, which should reduce the potential for this type of bias.

Microbial resistance to the selected antibiotic treatment has been shown to increase the risk of failure for patients with intraabdominal infections. Patients in PRTs had a lower incidence of resistance, which may be due to better antibiotic selection or a less severe disease process. Enrollment in a clinical trial regulates drug selection and may ensure that more effective antibiotics are prescribed initially.

Ineffective empirical antimicrobial therapy has been associated with a greater likelihood of treatment failure in patients with peritonitis 25 and other infections.

This factor, combined with the increased monitoring of care by clinical investigators and research nurses, may account for the better outcomes of patients enrolled in PRTs.

Lead-time bias is a well-described phenomenon in screening studies. Protocols generally require immediate screening of patients with the index disease for enrollment into a trial. Delays in patient presentation and disease recognition may ultimately lead to the exclusion of a patient from trial participation.

For example, a patient may enter the hospital with normal renal function, and subsequently peritonitis may develop. A delay in recognition of the infection causes renal function to worsen. If this patient were not immediately screened for enrollment, the subsequent impairment of renal function would lead to exclusion from participation in a trial. A primary goal of a clinical trial is to select similar groups of patients with a relatively uniform disease process for each treatment arm.

The development of homogeneous treatment groups generally is accomplished through the process of randomization, 28 which reduces systematic bias and equally distributes patients with known and unknown risk characteristics into the various treatment arms. Randomization takes place, however, only after patients have been screened for all potential exclusion criteria; this is an important point that often is not considered. Thus, the treatment arms are balanced with similar groups of patients derived from a homogeneous patient population with a lower severity of disease.

The risk characteristics of patients excluded before randomization are not routinely recorded or analyzed, and the treatment results of these patients have not been reported. Clinical trial investigators attempt to ensure a relatively uniform patient population by carefully controlling enrollment through the establishment of restrictive inclusion and exclusion criteria. One approach is to establish rigid criteria; this leads to a more homogeneous study population and ensures that the observed treatment effect is robust and incontrovertible.

Alternatively, the use of less restrictive eligibility criteria selects a more heterogeneous patient population. This approach requires a more sophisticated stratification system based on patient risk factors to analyze the results properly.

The expense and time involved in conducting a carefully designed clinical trial can be enormous, and therefore the need to find a clear treatment effect favors enrollment of a homogeneous patient population. Under these circumstances, there is a risk of limiting the applicability of the results to other patients who have a similar disease but who were excluded from the study.

Better record keeping and the more extensive collection of additional clinical data allows more accurate risk adjustment in a larger, more heterogeneous patient population. This approach excludes fewer patients and favors the applicability of study findings to a broader group of patients. The results of the current study show that the degree of illness as measured by admission APACHE II score, the presence of antimicrobial resistance on initial culture, and enrollment into a PRT were significant determinants of cure and ultimate survival for patients with serious intraabdominal infections.

As surgeons, we can exercise some control over each of these parameters. Although the severity of illness is often determined at the time the patient is initially seen, avoiding delays in treatment as well as prompt resuscitation and support of organ systems may reduce treatment failure by preventing further physiologic derangements.

The proper selection of antimicrobial agents for the treatment of intraabdominal infections should minimize the occurrence of antibiotic resistance. The advantages of being enrolled in a PRT may relate to the mandated selection of empirical antibiotic dose and therapy, or to improved delivery of care. Although the exact cause cannot be determined at present, these observations nevertheless show a benefit to study participation, which is a key element of informed consent.

We hope that these observations will stimulate further investigations of this and other possible benefits of PRT participation. Some patients are excluded from study participation because of associated organ dysfunction, such as severe renal or hepatic failure. These diseases often require dosage adjustment of antimicrobial agents, which may lead to subtherapeutic drug concentrations and thus reduce their effectiveness.

Other exclusion criteria prohibit the enrollment of patients with compromised immune function, because these patients have a greater risk of treatment failure. It may be more relevant to avoid the routine exclusion of more seriously ill patients, instead using more rigorous methods to stratify risk characteristics. This would provide a more realistic assessment of the expected outcomes for more seriously ill patients and would improve the external validity and applicability of the results of clinical trials.

Louisville, Kentucky : Dr. Aust, Dr. Townsend, ladies and gentlemen. Mark is to be congratulated for taking up a tough subject. This has been in the background of many clinical trials for a long time. In fact, it was about 20 years ago before this Association when Dr. Stone, perhaps with Dr. He assumed at the time and discussed briefly that this was because they got better care, the study coordinator was looking after them, the professor was interested, and all the other factors Mark has described.

Mark took this a very important further step today, because he says it is not just that. When I looked at the manuscript, it says these patients are younger, they are less sick, and that those two factors directly lead to shorter stay, less antibiotic resistance and less frequency of a whole variety of interventions.

This is often ensured by using automated randomization systems e. RCTs are often blinded so that participants and doctors, nurses or researchers do not know what treatment each participant is receiving, further minimizing bias.

RCTs can be analyzed by intentionto-treat analysis ITT; subjects analyzed in the groups to which they were randomized , per protocol only participants who completed the treatment originally allocated are analyzed , or other variations, with ITT often regarded least biased. All RCTs should have pre-specified primary outcomes, should be registered with a clinical trials database and should have appropriate ethical approvals.

RCTs can have their drawbacks, including their high cost in terms of time and money, problems with generalisabilty participants that volunteer to participate might not be representative of the population being studied and loss to follow up. While expensive and time consuming, RCTs are the gold-standard for studying causal relationships as randomization eliminates much of the bias inherent with other study designs. To provide true assessment of causality RCTs need to be conducted appropriately i.

Disclosures: The authors have no financial interests to disclose. National Center for Biotechnology Information , U. Author manuscript; available in PMC Dec 1.

Locascio , PhD 2.