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

Cait SE O’Sullivan, PharmD (biography, no disclosures)

What I did before

I used to be too easily persuaded about the benefits and harms of a drug therapy on the basis of single randomized controlled trial.

What changed my practice

A 2014 analysis tested the durability of strong recommendations across American College of Cardiology/American Heart Association (ACC/AHA) clinical practice guidelines [1]. Across 11 ACC/AHA guidelines, researchers identified 619 strong recommendations which according to the ACC/AHA indicates that a “procedure/treatment should be performed/administered”. In subsequent guideline updates, 80% of these recommendations were retained while 20% were downgraded, reversed or entirely omitted. The accompanying editorial affected me: “these omissions were usually unexplained: the recommendations simply disappeared” [2]. Recommendations were more likely to be downgraded, reversed or omitted if they were supported by opinion, observational data, or a single randomized controlled trial as compared to recommendations supported by multiple trials [1].

During a 2016 U.S. Food and Drug Administration (FDA) advisory committee meeting which considered the addition of a cardiovascular mortality risk reduction claim for the glucose lowering medication empagliflozin, an FDA Director explained [3]: “The scientific basis for requiring two studies is grounded in the fact that chance, biases, biologic variability, generalizability issues for other factors inherent to the single positive trial, could lead to an erroneous conclusion that the drug is effective when in fact it is not” [4].

What I do now

Using an example: The 2016 Canadian Cardiovascular Society (CCS)’s Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult includes this recommendation: “We recommend ezetimibe as second-line therapy to lower LDL-C levels in patients with clinical CVD if targets are not reached with maximally tolerated statin therapy (Strong Recommendation; High-Quality Evidence)” [5]. The CCS reports applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology [6]. Using this framework, the CCS’s ezetimibe recommendation denotes the following:

As supportive evidence, the CCS guideline references a randomized controlled trial: “Ezetimibe added to statin therapy after acute coronary syndromes” (IMPROVE-IT trial) [7]. The guideline explains: “This is the first time that a nonstatin, when combined with a statin in high-risk patients, resulted in a significant (albeit relatively small) reduction in clinical events (NNT = 70)” [5].

When I identify strong drug therapy recommendations of particular relevance to my practice scope, I seek collateral information and there are two resources I routinely incorporate into my literature search. I start with the Cochrane Library and then check to see whether a FDA advisory committee has weighed in on key issues.

1. Search the Cochrane Library for a systematic reviewThe Institute of Medicine’s 2011 Standards for Developing Trustworthy Clinical Practice Guidelines emphasize: “To be trustworthy, guidelines should be based on a systematic review of the existing evidence” [8]. A search for “ezetimibe” in the Cochrane Library identifies a relevant systematic review: “Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events” [9].Link to Cochrane Library: http://www.cochranelibrary.com/.This review is currently at the protocol stage however I can see in the publicly-accessible protocol that the authors have explicitly specified their outcomes of interest [9]. I can expect the review to clearly report the effects of ezetimibe on each of these outcomes as well as the quality of the evidence. This would add clarity to the CCS’s statement that the addition of ezetimibe results in a “reduction in clinical events” [5]. The review’s main results, conclusions, and plain language summary will be accessible without a subscription whereas access to the full review generally warrants a subscription (e.g., through university or health authority libraries). Access is also available to registrants of the College of Physicians and Surgeons of British Columbia.
2. Search for a U.S. Food and Drug Administration advisory committee meeting For newly approved drugs or new indications, the FDA database can yield a wealth of publicly-accessible information particularly if an advisory committee meeting has been convened as part of the regulatory review [10]. This stands in contrast to Health Canada’s drug database [11]. A now-retired FDA medical team leader advised when I asked about locating these meeting materials systematically: “Google it”. Indeed, a search “fda meeting materials ezetimibe IMPROVE- IT” quickly identifies that the FDA convened an Endocrinologic and Metabolic Drugs advisory committee on December 14, 2015. Using these two details: 1. the specific committee; 2. the meeting date, the relevant FDA advisory committee can be selected with links to various meeting materials [12].Link to U.S. Food & Drug Administration Human Drug Advisory Committees: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/default.htm.For a quick snapshot of the committee’s deliberations, the minutes include a synopsis of the discussions and vote … a short read: approximately 3 pages of content [13].Link to the Minutes: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM484885.pdf.Four discussion questions address the efficacy and safety results, subgroup analyses, and methodological limitations of the IMPROVE-IT trial. They also consider whether evidence from the specific clinical setting of the IMPROVE-IT trial (recent acute coronary syndrome) could be extrapolated to persons with stable coronary heart disease. There was a single voting question: “Do the efficacy and safety data from the IMPROVE-IT trial provide substantial evidence to support approval of a claim that adding ezetimibe to statin therapy reduces the risk of cardiovascular events?” [13].

   In apparent contrast to the CCS’s strong recommendation, the FDA’s advisory committee voted in the majority against a cardiovascular risk reduction claim for ezetimibe when added to statin therapy. The committee included patient representatives as well as experts in cardiology, epidemiology, endocrinology, and statistics. Click on the link to the minutes to quickly view an account of the five YES votes and ten NO votes.For readers with time and curiosity, the FDA meeting materials also include: briefing information developed separately by FDA medical reviewers and the drug sponsor, a transcript of the committee meeting (including who voted how and why), and the FDA and the drug sponsor’s presentation slides [14-16].

Conclusion

With little practice, Cochrane review summaries and FDA advisory committee minutes can be accessed efficiently. These two resources may not address every new medication or expanded indication, but when they do, they add important texture to my comprehension beyond that provided by clinical practice guidelines. While exploring the hundreds of pages of FDA advisory committee meeting materials in its entirety is impractical for most clinicians, it is reasonable for us to ask our academic and clinical leaders to have invested in this additional work.

Acknowledgements: Linda Brown (MSc), Ruth Campbell (BScPh), Tom Perry (MD), Aaron Tejani (PharmD) for their constructive peer reviews.

Additional Resources

“What is Cochrane evidence and how can it help you?” http://www.cochrane.org/what-is-cochrane-evidence

References

1. Neuman MD, Goldstein JN, Cirullo MA, Schwartz JS. Durability of class I American College of Cardiology/American Heart Association clinical practice guideline recommendations. JAMA. 2014;311(20):2092-2100. (View) DOI: 10.1001/jama.2014.4949
2. Shekelle P. Updating practice guidelines. JAMA 2014;311(20):2072-2073. (Request from CPSBC or view with UBC) DOI: 10.1001/jama.2014.4950
3. 2016 Meeting materials, endocrinologic and metabolic drugs advisory committee. USA Food and Drug Administration. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm491062.htm. Updated May 25, 2017. Accessed May 31, 2017. (View)
4. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Endocrinologic and metabolic drugs advisory committee (EMDAC) meeting [Transcript]. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM522096.pdf. June 28, 2016. Accessed May 31, 2017. (View)
5. Anderson T, Gregoire J, Pearson G, Barry A, Couture P, Dawes M, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 2016;32(11):1263-1282. (Request from CPSBC or view with UBC) DOI: 10.1016/j.cjca.2016.07.510
6. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADE Handbook. http://gdt.guidelinedevelopment.org/app/handbook/handbook.html. Updated October 2013. Accessed May 31, 2017. (View)
7. Cannon C, Blazing M, Guigliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 2015;372(25):2387-2397. (View) DOI: 10.1056/NEJMoa1410489
8. Clinical Practice Guidelines We Can Trust. Institute of Medicine. http://iom.nationalacademies.org/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx. Published March 23, 2011. Accessed May 31, 2017. (View)
9. Zhan S, Xia P, Tang M, Liu F, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events (Protocol). Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD012502. (View) DOI: 10.1002/14651858.CD012502.
10. Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf. Accessed May 31, 2017. (View)
11. Habibi R, Lexchin J. Quality and Quantity of Information in Summary Basis of Decision Documents Issued by Health Canada: e92038. PLoS One. 2014;9. (View) DOI: 10.1371/journal.pone.0092038
12. 2015 Meeting materials, endocrinologic and metabolic drugs advisory committee. USA Food and Drug Administration. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm426278.htm. Updated May 25, 2017. Accessed May 31, 2017. (View)
13. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM484885.pdf. December 14, 2015. Accessed May 31, 2017. (View)
14. Briefing information for the December 14, 2015 meeting of the endocrinologic and metabolic drugs advisory committee (EMDAC). U.S. Food and Drug Administration. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm476504.htm. December 14, 2015. Accessed May 31, 2017. (View)
15. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Endocrinologic and metabolic drugs advisory committee (EMDAC) meeting [Transcript]. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM484886.pdf. December 14, 2015. Accessed May 31, 2017. (View)
16. Slides for the December 14, 2015 meeting of the endocrinologic and metabolic drugs advisory committee (EMDAC) USA Food and Drug Administration. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm478548.htm. Updated December 21, 2015. Accessed May 31, 2017. (View)

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

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