Which adverse effects are significant to patients in PACE?

This clinic did not cover questions in regard to funding, research or complaints against the NHS. Such questions need to be addressed to the local GPC (General Practitioner Council). However as there was so much interest on these subjects we have left many of them under this heading for viewing but they are intentionally not answered by the panel.

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by biophile.pr on Tue Aug 20, 2013 3:33 am

Which adverse effects are significant to patients in PACE?

White et al have repeatedly re-assured us that GET is safe. However, patients and researchers may have different ideas about what constitutes a significant adverse effect, and this difference may help in part to explain the noted "discrepancy" between patient surveys and the PACE Trial.

PACE have given their definition for serious adverse events:
"(a) Death; b) Life-threatening event; c) Hospitalisation (hospitalisation for elective treatment of a pre-existing condition is not included), d) Increased severe and persistent disability, defined as a significant deterioration in the participant’s ability to carry out their important activities of daily living of at least four weeks continuous duration; e) Any other important medical condition which may require medical or surgical intervention to prevent one of the other categories listed; f) Any episode of deliberate self-harm."
PACE have given their definition for serious deterioration:
"… defined as any of the following outcomes: a short form-36 physical function score decrease of 20 or more between baseline and any two consecutive assessment interviews; scores of much or very much worse on the participant-rated clinical global impression change in overall health scale at two consecutive assessment interviews; withdrawal from treatment after 8 weeks because of a participant feeling worse; or a serious adverse reaction."
All other adverse events which did not meet this criteria were apparently regarded as safe and insignificant. Some of these measures required sustained severe worsening over a long period of time.

White et al stated in their recent response on this forum that there were no significant differences in "any" of the safety measures across the four trial arms (except for the measure of satisfaction in the SMC-alone group), which presumably also includes "serious adverse events" (SAEs) since they listed it in the same paragraph among the other safety measures.

However, this contradicts their 2011 Lancet paper which states that "There were more serious adverse events in the GET group than there were in the SMC group (p=0·0433)." An effect size for this statistically significant difference is not given, but when looking at Table 4, it appears that SAEs were roughly 2.4 times more common for +GET than for SMC-alone, although confidence intervals seem somewhat high.

But were these events related to GET or just a (statistically significant) "coincidence"? Serious adverse reactions (SARs) are SAEs which were later judged to be related to therapy. Coincidently, once "independent assessors" were unblinded to participant allocation in order to judge whether SAEs were the result of therapy or not, this significant difference between +GET and SMC-alone just disappeared.

Therefore, patients considering GET need to know that it was these trial assessors which consciously decided whether GET was safe or not in the PACE Trial. In fact, the +GET participants themselves demonstrated a statistically significantly higher number of serious adverse events. These may not have been common, but they occurred nevertheless.

So what about "non-serious" adverse events, which patients themselves may still deem important to them even if researchers do not when researching their pet therapies? PACE reported that there was no significant difference between groups. However, the collected data on these particular events had also been graded for severity (so it was possible to have a severe non-serious adverse event), but in the 2011 Lancet paper all these types were lumped together without any consideration for severity, and so far there has been no data published on the number of these events judged to be a result of therapy.

The threshold for harm was much higher than the threshold for improvement. During the changes to the protocol, the threshold for harm was raised further while the threshold for improvement was lowered. We are still waiting for the promised data on deterioration as defined as the opposite of improvement to fatigue and physical function. Unfortunately, this data will be for 52 weeks follow-up, 6 months after therapy, which may be enough time for patients to recover from any deterioration they experienced.