Per-protocol population

Please provide a definition of the per protocol population and the intention to treat population Per protocol population Intention to treat population... 

In explanatory trials, we are hkely to exclude both protocol violators and treatment non-compliers. The objective behind these exclusions is to increase the efficiency. However the exclusions may give rise to bias and hence to compromise the results if too many patients are excluded. Such an analysis population is termed as completers, or per protocol, population. In pragmatic trials, we generally include all patients using the intention-to-treat (ITT) principle. 

There are a number of issues in using such studies to achieve marketing authorisation. First, there needs to be a justification of the boundaries. Flow can we be sure that the choice of S is appropriate Second, has an appropriate choice comparator been made Is the dose of the comparator appropriate Is the population of patients appropriate Third, while for superiority trials it is generally accepted that the appropriate analysis population is an ITT population, it has been argued that for equivalence and non-inferiority studies that the as per protocol population also has a role to play. Finally we need to be sure that an equivalence or non-inferiority study is... 

The Per-protocol population is comprised of subjects whose participation and involvement in the trial was compliant with all of the requirements and activities detailed in the study protocol. The per-protocol population is a specified subset of the ITT population Subjects who are not compliant are excluded from the per-protocol data set. It should be noted that it is not simply subjects themselves that cause deviations from the protocol An investigator can also be responsible for not conducting parts of the trial appropriately. It was noted in Section 5.7.2 that excessively long study protocols can be associated with lack of compliance on the part of the investigators. Exclusion of subjects whose activities violated the protocol because the investigator did not conduct part of the trial properly is a very real outcome of this problem. 

In contrast to the conservative ITT analysis, analysis of the per-protocol population may maximize the opportunity to demonstrate efficacy the per-protocol population is the population in which the treatment is likely to perform best. Adherence to the protocol may be related to the treatment and outcome (Kay, 2005). This is why the per-protocol analysis is considered secondary to the more conservative ITT analysis. 

The per-protocol population (also known as the efficacy or evaluable population) This is also a subset of the ITT population, and comprises individuals whose participation and involvement in the trial were considered to comply with significant requirements and activities detailed in the study protocol. Participants would typically be excluded from the per-protocol population if they exhibited poor dosing compliance, missed a number of clinic visits, or used prohibited medications that may interfere with the evaluation of the test treatment. 

Both the ITT and the safety populations can be used in the analysis of safety data. The ITT and per-protocol population are typically used in the analysis of efficacy data. 

Using both ITT and per-protocol populations in efficacy analyses... 

In therapeutic confirmatory trial efficacy, the same analyses are typically conducted twice, using data from the ITT population and data from the per-protocol population (see Turner, 2007). The analyses conducted using the ITT population are considered to be the primary analyses because ITT analysis provides a conservative strategy in the sense that it tends to bias against finding the results that the researcher... 

Is the per-protocol population a lot smaller than the ITT population (it will almost certainly be somewhat smaller) ... 

The ITT analysis population and the per-protocol (efficacy or evaluable) population are typically used in efficacy analyses. As described in the previous chapter, the ITT population comprises all subjects in a clinical trial that were randomized to a treatment group, regardless if any data were actually collected from them. 

For many reasons, there are likely to be more than one publication that address the same research question. Even when the results are not identical (which is very likely to be the case), consistency in the interpretation of the results is reassuring Recall the discussion of consistency between ITT and per-protocol analyses in Section 11.2.3. Additionally, results from many smaller studies that are inconclusive can sometimes be combined to paint a picture that is very compelling, and the overall result can be put in a broader context, since it has been attained from different treatment regimens and different subject populations (Matthews, 2006). 

For the per-protocol analysis population of 11 patients, the mean plasma half-life was 10.48 1.6 h, and adjusted recovery 2.0 0.5 lU dL plasma per lU kg body weight infused. These data are consistent with those seen in adolescents and older patients, when the greater weight-adjusted plasma volumes that affect the volume of distribution and adjusted recovery in young children, as well as potentially alter halflife, are taken into account [32]. 

Therefore, an algorithm has to be developed to precisely define how each analysis population of the dataset is defined. For example, there are at least four analysis population datasets, e.g. the intent-to-treat (ITT) population, the per-protocol (PP) population, the safety population, and the microbiological population, as indicated in the diagram (Figure 22.2). During the derivation of various analysis populations, it may be necessary to issue new... 

Sanchez, M.M., Chen, X. Choosing the analysis population in non-inferiority studies Per protocol or intent-to-treat. Statistics in Medicine 25 1169-1181,2006. 

Fig. 7. Percentage of surgical patients avoiding donor blood transfusion in the protocol-defined target population (blood loss >20 ml per kilogram body weight) from postoperative day 1 through day 21 (or hospital discharge). First bar is the Oxygenf-treated patients second bar, control group ( p<0.05 between groups). From Ref. [27], with permission.

In recent clinical and preclinical work, researchers at Pharmacyclics Inc., have demonstrated that texaphyrins selectively localize in atheromatous plaque and not in the normal aortic wall [243,300,301]. In the case of gadolinium texaphyrin PCI-0120 (3), this has been shown in human populations via MRl. With lutetium texaphyrin PCI-0123 (4), spectral bioimaging of intact rabbit aortas (i.e. after PCI-0123 injection and subsequent sacrifice) served to reveal plaque-to-normal vessel retention ratios on the order of 34 to 1 [300]. Further, extensive preclinical studies have helped establish that PCI-0123 (4) may be used in a PDT sense to effect selective photodamage of atheromatous plaque lesions in diet-induced hypercholes-terolemic New Zealand white rabbits [243,300,301]. For instance, Woodbum et al. reported that a protocol involving i.v. injection of PCI-0123 (lOpmolkg per day... 

Different centers often draw subjects from different types of patient populations. Also, different centers may utilize different procedures and medical practices that are not controlled by the study protocol. It is, therefore, reasonable to expect that the within-center variability is smaller than the overall variability. In a multicenter trial, the center often serves as a stratification variable, thereby reducing the variability and increasing the efficiency of the trial design. In order to take advantage of this aspect of the multicenter trial, the number of subjects per center cannot be too small so that the estimate of the intra-center variability is stable. A rule-of-thumb is that the number of subjects per treatment group within each center will be at least 5. 

The annual incidence of TB in the United States declined by about 5% per year from 1953 to 1983 (Fig. 110-1). In 1984, this decline slowed, and then the incidence of TB rose from 1988 to 1992, reaching 10.5 cases per 100,000 population. Since 1992, more effective infection control practices and treatment protocols have reduced TB rates to 5.2 per 100,000 population as of 2002. Despite this good news, the eradication of TB from the United States will remain very difficult. One reason is that we continue to import new cases from countries where TB remains out of controU ... 

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