Per-protocol set

ICH E9 (1998) Note for Guidance on Statistical Principles for Clinical Trials  

The definition of a per-protocol set of subjects allows us to get closer to the scientific question by including only those patients who comply with the protocol to a defined extent. The per-protocol set, like the full analysis set, must be prespecified in the protocol and then defined at the patient level at the blind review, following database lock, but before breaking the blind. It must be noted, however, that the per-protocol set is subject to bias and further, tends to overestimate the treatment effect. For this reason it is usually used only as a secondary analysis, supportive hopefully of the findings based on the full analysis set. 

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This regulatory statement is not saying that the analyses based on the full analysis set and the per-protocol set are in any sense co-primary. The full analysis set will provide the primary analysis and usually this analysis must give p < 0.05 for a positive result. The per-protocol set, however, does not need to give p < 0.05, but should provide results which are qualitatively similar in terms of the direction of the treatment effect and with effect size not too dissimilar from that seen for the full analysis set. 

When the full analysis set and the per-protocol set lead to essentially the same conclusions, confidence in the trial results is increased... ... 

The discussion in the previous section regarding the practical application of the principle of intention-to-treat does not, however, give the full picture. While this principle plus consideration of the per-protocol set may clearly define the sets of subjects to be analysed, we still have to decide how to deal with the missing data caused by failure to complete the study entirely in line with the protocol. 

Does basing the sample size calculation on the per-protocol set and then increasing the sample size to allow for dropouts ensure that the per-protocol set will not be subject to bias ... 

No It often makes sense to power for the per-protocol set and then factor upwards to allow for dropouts as this will also ensure that there is enough power for the full analysis set providing any extra patient-to-patient variation in the full analysis set does not counterbalance the increase in sample size, but the analysis based on the per-protocol set is still subject to bias. See Section 8.5.2 for further discussion on this point. 

Generally speaking we power based on the per-protocol set and then increase the sample size requirement to give the number required in the full analysis set. Under some circumstances, for example in anti-infective trials, we factor up further to take into account the patients that are recruited, but are not eligible for the full analysis set. 

In a similar way it may be that the crd seen in the analysis based on the per-protocol set is larger than that seen in the full analysis set and this anticipated difference may also need to be factored in. 

The trial appears to have been powered in terms of the per-protocol set. Recruitment was set at 255 patients to allow for dropouts. 

In a superiority trial the primary analysis will be based on the full analysis set with the per-protocol set being used as the basis for a supportive secondary analysis, and in this sense there will be no multiplicity issues. The form of the analysis, however, depends in addition on the methods to be used to account for missing data and these should clearly be pre-specified. It is also good practice to explore the robustness of the conclusions to both the choice of the per-protocol set and the methods to be used for missing data. These analyses again will be supportive (or not) of the main conclusions and no multiplicity aspects arise. 

In equivalence and non-inferiority trials (see Chapter 12), the full analysis set and the per-protocol set have equal status and are treated as co-primary. The requirement, therefore, is to show significance for each of these analyses. This is another case where significance is needed on all endpoints with both analyses being conducted at the usual 5 per cent significance level. 

For equivalence and non-inferiority trials, therefore, the regulators like to see analyses undertaken on both the full analysis set and the per-protocol set with positive conclusions being drawn from both. In this sense these two analyses are considered co-primary. There is a common misconception here that for equivalence/non-inferiority trials the per-protocol set is primary. This is not the case. The per protocol set is still potentially subject to bias because of the exclusion of randomised patients and so cannot supply the complete answer both analysis sets need to be supporting equivalence/non-inferiority in order to have a robust conclusion. 

As with sample size in superiority trials we generally power on the basis of the per-protocol set and increase the sample size to account for the non-evaluable patients. This is particularly important in non-inferiority trials where the full analysis set and the per-protocol set are co-primary analyses. Note also, as before in superiority trials further factoring up may be needed if there are randomised patients who are being systematically excluded from the full analysis set, as is the case, for example, in anti-infective trials. 

Definition of analysis sets (full analysis set, per-protocol set, safety set)... 

The per-protocoT set of subjects, sometimes described as the valid cases, the efficacy sample or the evaluable subjects sample, defines a subset of the subjects in the full analysis set who are more compliant with the protocol... ... 

In general, it is advantageous to demonstrate a lack of sensitivity of the principle trials results to alternative choices of the set of subjects analysed. In confirmatory trials it is usually appropriate to plan to conduct both an analysis of the full analysis set and a per-protocol analysis, so that any differences between them can be the subject of explicit discussion and interpretation. ... 

One very simplistic way of handling missing data is to remove those patients with missing data from the analysis in a complete cases analysis or completers analysis. By definition this will be a per-protocol analysis which will omit all patients who do not provide a measure on the primary endpoint and will of course be subject to bias. Such an analysis may well be acceptable in an exploratory setting where we may be looking to get some idea of the treatment effect if every subject were to follow the protocol perfectly, but it would not be acceptable in a confirmatory setting as a primary analysis. 

Gallium Nitrate (Ganite) [Hormone] Uses T Ca2+ of malignancy bladder CA Action X- bone resorption of Ca2+ Dose T Ca2+ 200 mg/m2/d x 5 d CA 350 mg/m2 cont inf X 5 d to 700 mg/m2 rapid IV inf q2wk in antineoplastic settings (per protocols) Caution [C, ] Do not give w/ live or rotavirus vaccine Contra SCr >2.5 mg/dL Disp Inj SE Renal insuff, X- Ca2+, hypophosphatemia, X- bicarb, <1% acute optic neuritis Interactions T Risks of nephrotox W/ amphotericin B,... 

Safety analysis patient set was defined as all patients who received the Biod/VTs/o Batimastat OC stent, per-protocol analysis patient set was defined as all patients in the Safety analysis set who did not deviate from the protocol. Categorical variables were summarized using counts and percentages. Continuous variables were summarized using mean, standard deviation, minimum and maximum, and median for variable not showing a normal distribution. For comparison of subgroups, the unpaired two-tailed student s t-test was used. Results were considered statistically significant at P< 0.05. 

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. 

The United States military operates an emergency fresh whole blood programme as a backup to stored blood. When these transfusions take place, donors and recipients are tested afterwards per a set protocol. The military reported the first case of transfusion-transmitted HTLV type I infection identified using this routine protocol [158 ]. 

Residue study protocols typically either include quality specifications for analytical procedures or refer to a written analytical method that includes such specifications. The protocol for an LSMBS should also include analytical quality specifications, either directly or by reference to a method. Analytical specifications usually include minimum and maximum recovery of analyte from fortified control samples, minimum number of such fortifications per set of samples, minimum linearity in calibration, minimum stability of response to injection of calibration solutions, and limits of quantitation and of detection. 

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