Limitation and possible additive value of real world evidence in comparison with randomized clinical trials


Authors: Ivan Tkáč
Authors‘ workplace: Excelentný tím pre výskum aterosklerózy (EXTASY), IV. interná klinika UPJŠ LF a UN LP Košice
Published in: Forum Diab 2021; 10(Suplement 1): 53-58
Category:

Overview

The results of randomized clinical trials (RCTs) are the gold standard needed to approve new drugs and the new treatment indications. Their limitation is that they do not fully reflect the population of all patients in the real clinical practice due to the limitations present in the inclusion and exclusion criteria. On the other hand, the randomization process ensures an almost perfect balance between known and unknown factors that could influence the outcome of the study. In recent years, studies analyzing patients from Real World Evidence (RWE) have been increasingly published, aiming to analyze more broadly defined patient populations than those tested in RCTs. Moreover, these studies do not require a longer period of time to conduct, as they are retrospective analyses based on electronic health record databases, insurance company data and other patient registries. The randomization process is replaced by the statistical method of propensity score matching. This method has its limitations, as the factors that are taken into account when creating similar pairs of patients are defined by the investigators based on their knowledge of known confounders, i.e. those factors that may influence the outcome of the study. Thus, unlike RCTs, RWEs are also unable to stratify the study population according to previously unknown confounders. The results of several RWEs were not later confirmed in RCTs. Also, RWE-based studies conducted after RCTs, and performed on a less risky population than in RCTs, often observed a larger effect of the investigational drug than in RCTs. This finding contradicts well-known observation that the effect of a drug is greater when studied in the population with higher risk. Hence, the data obtained by such studies can be considered complementary to those obtained in RCTs. Their additive value can be used to rationalize the change of the dose of the drug or the route of administration, as well as the use of the drug in a new patient population. RWE is not suitable for demonstrating the effect or safety of a new drug, nor for comparing different groups of drugs in relation to predefined study results. These results can be considered at most hypothesis-generating and require confirmatory RCTs or indirect comparison of groups of drugs using a meta-analysis.

Keywords:

antidiabetic therapy – GLP-1 receptor agonists – randomized clinical trials – real world evidence studies – SGLT2 inhibitors


Sources
  1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356(24): 2457–2471. Dostupné z DOI: <https://doi: 10.1056/NEJMoa072761>.
  2. Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393 (10166): 31–39. Dostupné z DOI: <https://doi: 10.1016/S0140–6736(18)32590-X>.
  3. Kristensen SL, Rørth R, Jhund PS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 7(10): 776–785. Dostupné z DOI: <https://doi: 10.1016/S2213–8587(19)30249–9>.
  4. Gerstein HC, McMurray J, Holman RR. Real-world studies no substitute for RCTs in establishing efficacy. Lancet 2019; 393(10168): 210–211. Dostupné z DOI: <https://doi: 10.1016/S0140–6736(18)32840-X>.
  5. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: II. Mortality results. Diabetes 1970; 19(Suppl 2): 785–830.
  6. Zheng SL, Roddick AJ, Aghar-Jafar R et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: A systematic review and meta-analysis. JAMA 2018; 319(15): 1580–1591. Dostupné z DOI: <https://doi: 10.1001/jama.2018.3024>.
  7. Eriksson JW, Bodegard J, Nathanson D et al. Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all causes mortality. Diabetes Res Clin Pract 2016; 117: 39–47. Dostupné z DOI: <https://doi: 10.1016/j.diabres.2016.04.055>.
  8. Rosenstock J, Kahn SE, Johansen OE et al. Effect of linagliptin vs glimepirid on major adverse cardiovascular outcomes in patients with type 2 diabetes. The CAROLINA randomized trial. JAMA 2019; 322(12): 1155–1166. Dostupné z DOI: <https://doi: 10.1001/jama.2019.13772>.
  9. Nyström T, Bodegard J, Nathanson D et al. Second line initiation of insulin compared with DPP-4 inhibitors after metformin monotherapy is associated with increased risk of all-cause mortality, cardiovascular events, and severe hypoglycemia. Diabetes Res Clin Pract 2017; 123: 199–208. Dostupné z DOI: <https://doi: 10.1016/j.diabres.2016.12.004>.
  10. Gerstein HC, Bosch J, Dagenais GR. [The ORIGIN Trial Investigators]. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319–328. Dostupné z DOI: <https://doi: 10.1056/NEJMoa1203858>.
  11. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117–2128. Dostupné z DOI: <https://doi: 10.1056/NEJMoa1504720>.
  12. Udell JA, Yuan Z, Rush T et al. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor. Results from the EASEL population-based cohort study (Evidence for Cardiovascular Outcomes with Sodium Glucose Contrasporter 2 Inhibitors in the Real World). Circulation 2018; 137(14): 1450–1459. Dostupné z DOI: <https://doi: 10.1161/CIRCULATIONAHA.117.031227>.
  13. Cavender MA, Norhammar A, Birkeland K et al. SGLT-2 inhibitors and cardiovascular risk. An analysis of CVD-REAL. J Am Coll Cardiol 2018; 71(22): 2498–2506. Dostupné z DOI: <https://doi: 10.1016/j.jacc.2018.01.085>.
  14. Suissa S. Reduced mortality with sodium-glucoes cotransporter-2 inhibitors in observational studies. Avoiding immortal time bias. Circulation 2018; 137(14): 1432–1434. Dostupné z DOI: <https://doi: 10.1161/CIRCULATIONAHA.117.032799>.
  15. Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: Real or bias? Diabetes Care 2018; 41(1): 6–10. Dostupné z DOI: <https://doi: 10.2337/dc17–1223>.
  16. Drucker DJ. The ascending GLP-1 road from clinical safety to reduction of cardiovascular complications. Diabetes 2018; 67(9): 1710–1719. Dostupné z DOI: <https://doi: 10.2337/dbi18–0008>.
  17. Longato E, Di Camillo B, Sparacino G et al. Cardiovascular outcomes of type 2 diabetic patients treated with SGLT-2 inhibitors versus GLP-1 receptor agonists in real life. BMJ Open Diab Res Care 2020; 8(1): e001451. Dostupné z DOI: <https://doi: 10.1136/bmjdrc-2020–001451>.
  18. Nørgaard CH, Starkopf L, Gerds TA et al. Cardiovascular outcomes with GLP-1 receptor agonists versus SGLT-2 inhibitors in patients with type 2 diabetes. Eur Heart J Cardiovasc Pharmacother 2021. Dostupné z DOI: <https://doi: 10.1093/ehjcvp/pvab053>. Ahead of print.
  19. Huang Y, Yuan W, Kohane IS, Beaulieu-Jones BK. Illustrating potential effects of alternate control populations on real-world evidence-based statistical analysis. JAMIA Open 2021; 4(2): 1–9. Dostupné z DOI: <https://doi: 10.1093/jamiaopen/ooab045>.
  20. U.S. Food & Drug Administration. Framework for FDA’s Real-World Evidence Program. December 2018. Dostupné z WWW: <https://www.fda.gov/media/120060/download>.
  21. Collins R, Bowman L, Landray M et al. The magic of randomization versus the myth of real-world evidence. N Engl J Med 2020; 382(7): 674–678. Dostupné z WWW: <https://doi: 10.1056/NEJMsb1901642>.
Labels
Diabetology Endocrinology Internal medicine
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