5 responses to “Seeking collateral information when clinical practice guidelines deliver strong recommendations for drug therapies on the basis of a single clinical trial”

  1. For BC physicians, a free source for Cochrane Library content including full text systemic reviews is the College of Physicians and Surgeons of BC library’s subscription to Evidence Based Medicine Reviews. Go to the bottom of the library’s Database webpage: https://www.cpsbc.ca/library/search-materials/databases

  2. I think Cochrane is a great second source, but personally I would be less trusting of the FDA. Sad as it is to say, so many bodies in the US these days are heavily influenced by lobbying and I am skeptical that the FDA would be immune to this. Having said that, the principle of checking a couple other reliable sources is still a good one to follow.

  3. I second Brett.
    Cochrane yes! But the FDA? They unleash these drugs with little data in the first place, then make it hard to find their revisions in the unlikely case they happen (absent deaths), as the article alludes to. “Google it”?

    Check out: http://www.bmj.com/content/357/bmj.j1680
    “Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review”

    Results: Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials).
    Conclusions: The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

  4. Excellent advice. The limitation is doing this at point of care.

  5. Thank you, Brett Broster and Derrick Moore, for submitting comments regarding the quality and quantity of evidence used to support drug approval. In my view, that is why there is value in exploring U.S. FDA regulatory materials which provide access to the evidence considered at the time of approval of a new drug therapy or new drug-therapy indication.

    Using another recent example:

    In February 2016, the Canadian Diabetes Association (recently rebranded Diabetes Canada) Clinical Practice Guidelines Expert Committee delivered this recommendation: “In people with clinical cardiovascular disease in whom glycemic targets are not met, an SGLT2 inhibitor with demonstrated cardiovascular benefit should be added to antihyperglycemic therapy to reduce the risk for cardiovascular and all-cause mortality (Grade A, Level 1A for empagliflozin)” [1]. The guideline’s reference is a single randomized controlled trial (EMPA-REG OUTCOME) published in the New England Journal of Medicine [2]. It was June 2016 when the FDA convened an advisory committee to review this claim and meeting materials became publically accessible then [3]. These materials include: a 152 page FDA medical review and 135 presentation slides; a 138 page drug sponsor review and 134 presentation slides; a 375 page meeting transcript. For clinicians, the short 8 page minutes can provide a starting point when considering exploring the materials further. The minutes include the vote on this question “Based on data in the briefing materials and presentations at today’s meeting, do you believe the EMPA-REG OUTCOME study results provide substantial evidence to establish that empagliflozin reduces cardiovascular mortality in the population studied?” YES votes = 12; NO votes = 11. This communicates to me that the evidence is not as straightforward as represented in the guideline.

    FDA materials generally provide more detail than the published version of a clinical trial but, unfortunately, systematic reviewers may not review these documents [3]. This deficiency recently became clearer when a cross-sectional analysis reported that research misconduct identified by the FDA rarely makes its way into the peer-reviewed literature [4]. This further informs changes in my practice which includes seeking diverse viewpoints and sources of information before reaching strong conclusions. I have described two diverse resources that I include in my search and I agree completely with Duncan Etches that delving this deeply is not possible at the point of care. Given this, a quick check of the reference list when reading (or when being detailed on) guidelines that make strong drug-therapy recommendations is a starting point …to see if they have.

    1. Diabetes Canada. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic Management of Type 2 Diabetes: February 2016 Interim Update. [Internet]. http://guidelines.diabetes.ca/browse/chapter13_feb-2016
    2. Zinman B et al. Empaglifozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
    3. U.S. Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee. June 28, 2016 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. [Internet].https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm491062.htm
    4. Turner E. How to access and process FDA drug approval packages for use in research. BMJ 2013;347:f5992. https://www.ncbi.nlm.nih.gov/pubmed/24126858

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