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IMMPACT recommendations: Interpreting the clinical importance of group differences in

Discussion in 'Other Health News and Research' started by Dolphin, May 29, 2011.

  1. Dolphin

    Dolphin Senior Member

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    This paper was referenced in the reply by the authors to the letters to the Lancet on the PACE Trial.

    None of it is specifically about ME/CFS so it is probably not going to be of interest to many/most.

    I underlined bits so thought I'd write them down somewhere for what they are worth.

  2. Dolphin

    Dolphin Senior Member

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    IMMPACT recommendations for individuals and groups are different
    (this is talked about more later)

    The second part of this paragraph discusses the some of the factors that can make up a positive increase in a trial:
    Comment: this would seem to suggest that the approach in the UK, where only studies of non-pharmacological rehabilitative interventions (and research relating to that model) are generally funded is a flawed model as is the health service only paying for those sorts of treatements.

    Currently because of the lack of biological research into ME/CFS (which some would like to continue), we don't have a good idea who might benefit from GET programs. Some people may claim everyone with chronic fatigue/chronic fatigue syndrome will benefit but this position I do not believe is justified.

  3. Dolphin

    Dolphin Senior Member

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    Thought I'd give the Conclusions its own section:
  4. oceanblue

    oceanblue Senior Member

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    This looks really interesting, but unfortunately my brain can't read the text with all those line-breaks, I find it too confusing...
  5. Dolphin

    Dolphin Senior Member

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    Are you talking about the abstract or the other posts? I'm not 100% sure what you are saying when you say "line breaks" - would you prefer if it went right the way over to the right hand side (like the last extract)?

    Or do you have characters when you read it that say <break> or <b> or whatever?
  6. oceanblue

    oceanblue Senior Member

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    When I copy/paste here the line breaks sort themselves out for some reason

    The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recently reviewed and
    recommended specific methods that can be used for interpreting the clinical importance of treatment outcomes for individual
    patients in chronic pain clinical trials [11]. These recommendations included a set of provisional benchmarks for interpreting
    changes in measures of pain, physical and emotional functioning, and global improvement that represent outcome domains
    recommended previously by IMMPACT [10] and [35]. The methods that were discussed for determining clinical importance and
    the recommended benchmarks all involved changes that occur within individuals from the beginning of a clinical trial to its
    conclusion. For example, decreases in patients pain intensity of >=30% were considered moderately important
    improvements, whereas decreases of >=50% were considered substantial improvements [11].
    The determination of criteria for clinically meaningful improvements for individual patients is necessary to categorize patients as
    responders or non-responders. Identifying which patients can be considered responders is often a critical aspect of
    interpreting clinical trial results. Responder analyses make it possible to compare the percentages of patients who achieve
    meaningful outcomes between treatment and control groups or between different treatment conditions, a readily interpretable
    approach to presenting clinical trial outcomes [13]. However, recommendations for determining clinically meaningful
    improvements in patients do not address an equally important consideration in the interpretation of clinical trial results
    specifically, what magnitude of difference between treatment groups should be considered clinically meaningful?
    In the IMMPACT recommendations describing the determination of clinically important changes for individual patients, the
    authors emphasized that the importance of group differences can only be established in the broader context of the disease
    being treated, the currently available treatments, and the overall riskbenefit ratio of the treatment [11,p. 108].

    The second part of this paragraph discusses the some of the factors that can make up a positive increase in a trial:
    One possible interpretation of the results of these clinical trials of OA knee pain and painful DPN is that the mean differences in
    response that were found between the treatment and placebo groups are not clinically meaningful. However, of existing
    pharmacologic treatments, acetaminophen and NSAIDs are internationally considered either first- or second-line for OA pain
    [1], [21] and [39] and duloxetine and pregabalin are internationally considered either first- or second-line for painful DPN [2], [9]
    and [25]. Of course, widespread clinical use does not provide evidence of clinical meaningfulness. If differences in mean
    response of the magnitude found in the trials of these medications were not considered clinically relevant benefits, however,
    clinicians would have limited therapeutic options for the pharmacologic treatment of these and other chronic pain conditions.
    It is not surprising that the improvements patients consider clinically meaningful are generally larger than the differences found
    between efficacious treatments and placebo in chronic pain clinical trials. Meaningful change in individual patients reflects any
    effects of the active treatment, placebo and other non-specific effects of the clinical setting, natural history and spontaneous
    resolution, and statistical regression to the mean. Differences between treatment and placebo groups, however, reflect the
    incremental benefits of active treatments that contribute to improvement after subtracting out placebo and other non-specific
    effects, natural history, and regression to the mean, for example, the pharmacologic effects of a medication. In addition, the
    differences between treatment and placebo groups in chronic pain clinical trials are limited by the magnitudes of the responses
    in the placebo groups, which can be substantial [22] and [26] and reflect multiple factors, especially placebo and other
    non-specific effects of clinical trial participation. Although these factors also affect response in patients receiving active
    treatment, a substantial response in the placebo group can attenuate the group difference with an active treatment if there is a
    floor below which treatment rarely reduces pain.


    In approximately half of patients with chronic pain, existing treatments are not effective or are poorly tolerated, and in patients
    who do respond, it is relatively rare for pain to be completely relieved or even reduced to mild severity. Because chronic pain
    treatments have incomplete efficacy, a treatment whose mechanism(s) of action is different from those of existing therapies
    may be effective in patients who are currently non-responders, presumably because the pathophysiologic mechanism of the
    patients pain is targeted by the new treatment and not by existing therapies. For similar reasons, treatments with a different
    mechanism of action could also be used in combination with existing therapies to augment treatment response in those patients
    who are partial responders [9]. Moreover, because chronic pain treatments are often poorly tolerated, a treatment with different
    mechanisms of action may be better tolerated by patients who cannot tolerate the adverse effects of existing therapies. For
    these reasons, the benefit of a treatment with a different mechanism of action from those of existing therapies could be
    considered more clinically meaningful than if the treatment had the same mechanism of action as existing therapies. (contd.)

    The limitations of any available treatments should also be taken into account when interpreting group differences. Specifically,
    a modest benefit compared with placebo may be more clinically meaningful if existing therapies have important limitations, such
    as poor safety and tolerability or limited efficacy, compared with a similar benefit occurring in a context of existing therapies that
    have excellent safety, tolerability, and efficacy.

    Comment: this would seem to suggest that the approach in the UK, where only studies of non-pharmacological rehabilitative interventions (and research relating to that model) are generally funded is a flawed model as is the health service only paying for those sorts of treatements.

    There are other factors specific to certain treatments that must be considered in evaluating the clinical meaningfulness of their
    benefits. These include an absence or limited number of drug interactions, especially because many chronic patients are older
    and may not only be receiving other analgesics but are likely to be taking a variety of non-analgesic medications. In addition,
    modest benefits with a treatment for which there is a simple test or procedure available that predicts whether a patient will have
    a positive therapeutic response (e.g., a trial of transcutaneous electrical nerve stimulation) may be more clinically meaningful
    than comparable benefits associated with a treatment for which response cannot be predicted. In many circumstances,
    patients, clinicians, and third-party payers would consider it beneficial to be able to predict therapeutic response because
    increasing the likelihood of a positive response reduces the time, risks, and expenses associated with therapeutic failure. (contd.)

    Currently because of the lack of biological research into ME/CFS (which some would like to continue), we don't have a good idea who might benefit from GET programs. Some people may claim everyone with chronic fatigue/chronic fatigue syndrome will benefit but this position I do not believe is justified.

    (contd.) Finally, any research design features of the clinical trial that could have attenuated the magnitude of the group difference in
    response must also be considered in its evaluation. For example, insufficient pain at baseline could make it difficult or even
    impossible for an active treatment to show greater reduction in pain compared with placebo. In addition, patients in placebo
    groups are likely to use more rescue medication than patients treated with efficacious analgesics, and it is certainly possible
    that a substantially greater use of rescue analgesics in a placebo group could attenuate the difference in pain relief compared
    with the active treatment. Of course, clinical meaningfulness cannot be attributed to a group difference simply because the trial
    has design limitations. However, such factors can provide possible explanations for more modest benefits than would otherwise
    have been expected and thereby provide a basis for conducting additional studies (ideally, without such limitations) to
    determine whether the magnitude of the treatment benefit has been underestimated.
  7. Dolphin

    Dolphin Senior Member

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    Hi oceanblue, you've genuinely lost me. Mine looks, to me, like it has exactly the same line breaks as yours has.
  8. Esther12

    Esther12 Senior Member

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    it could be that you've got different sized screens, and it's auto-formatting. I've not read this properly yet, but thanks for posting it up.
  9. Dolphin

    Dolphin Senior Member

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    Are you saying that what I posted looks bad to you? What is happening - are there short lines and long lines?

    I generally look at things (and post things) in IE at 100% so I've just opened it in Opera and the line breaks look the same to me as what oceanblue posted.
  10. oceanblue

    oceanblue Senior Member

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    Weird. I use firefox, and the copy/paste fixed the line breaks in firefox, but problem remained in IE.

    Anway, I was particularly interested in the point that therapies with different modes of working are more valuable due to possibility of complementarity (for responders to other types of treatment) or as an alternative approach for non-responders to other therapy types.

    I think Marco posted on the issue of asking patients to establish what counts as 'clinically useful'; what a radical idea.
  11. Dolphin

    Dolphin Senior Member

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    Thanks. Still not 100% sure what the problem is - short and long lines?

    Yes, it's interesting.

    Ok.

    It also comes up in a paper I posted on recently:
    http://forums.phoenixrising.me/show...ient-reported-outcome-measures-used-in-CFS-ME
    Quality and acceptability of patient-reported outcome measures used in CFS/ME

    Here are the last two paragraphs of discussion section - they give an idea of the paper and hopefully how it chimes in with what you are saying:

  12. Esther12

    Esther12 Senior Member

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    To try to clarify (this isn't important though), this is how it looks to me:

  13. Dolphin

    Dolphin Senior Member

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    Ok, thanks - that's what I meant by "short and long lines".

    I don't want that to happen on lots of threads - what browser do you use?
  14. Esther12

    Esther12 Senior Member

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    I use firefox.

    Would the screen size not matter more though? eg: If the lines fitted in okay, it wouldn't matter. I may have my text size higher than normal too.

    I don't normally find it a big problem.
  15. Dolphin

    Dolphin Senior Member

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    Thanks for that. I just downloaded Firefox to check (I know this has been a been a big Firefox plot involving you and oceanblue ;) ). It still looks fine for me - that is to say, what I posted is quite even on the right hand side (and it doesn't go write the way across .

    But it could be to do with screen size as you mention. Actually, as I write this in the advanced mailing box, below, I can see short and long lines for my previous posts except where I pasted the Conclusions.

    Anyway, Esther12 and oceanblue, feel free to alert me to this in future and I'll see what I can do. Perhaps I did something last night specifically.

    If anyone with IT knowledge can lead this blind man, I'd be interested in hearing.

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