From Clinical Trials to Clinical Guidelines: Reconciling the Evidence Work Group #2

Transcription

1 From Clinical Trials to Clinical Guidelines: Reconciling the Evidence Work Group #2 ISAPP 10 th Anniversary Meeting Cork, Ireland October 3,

2 Workgroup #2 Dan Merenstein, MD (Washington, USA) Michael Cabana, MD (San Francisco, USA) Andi Shane, MD, MPH (Atlanta, USA) Hania Szajewska, MD (Warsaw, Poland) Amnon Lahad, MD (Jerusalem, Israel) Alex Krist, MD, MPH (Richmond, USA) Girish Deshpande, MD (Sydney, Australia) Frank D Amico, PhD (Pittsburgh, USA) Joe Neu, MD, PhD (Gainesville, USA) Tammy Ringel, MD, MPH (Chapel Hill, USA) Steven Davis, PhD (Columbus, USA) Arthur Ouewhand, PhD (Finland) Niklas Larsson (Sweden) Kurt Selle (Chapel Hill, USA) Francois-Marie Luquet (Israel) Alexndra Meynier (France) Dan Tancredi, PhD (Davis, USA) 2

3 Background Clinicians increasingly rely on experts and metaanalysis to provide guidelines for the use of probiotics There are relatively few well-done RCTs conducted for probiotic interventions in humans The current literature regarding the use of probiotics for the prevention of NEC illustrates the difficulty in translating clinical trial information to clinical guidelines 3

4 Necrotizing Enterocolitis (NEC) NEC is a spectrum of intestinal conditions affecting premature infants Pathogenesis of classic NEC is multifactorial, but some factors (e.g., GI microbial ecology) may be more important than others In US and Canada, it affects approximately 7% of babies weighing between grams Mortality is approximately 20-30% Very costly with significant sequelae

5 Classic NEC A B C Neu, J. and Walker, W. A. New England Journal of Medicine, Jan. 2011

6 Randomized Clinical Trials (RCTs) Despite limitations, randomized clinical trials (RCTs) produce the most highly regarded evidence. Provides robust, causal evidence Influences clinical practice Can help satisfy regulatory bodies with regard to health claims Helfand M, Balshem H. Principles in developing and applying guidance. In: Agency for Healthcare Research and Quality. Methods Reference Guide for Comparative Effectiveness Reviews [posted August 2009]. Rockville, MD. Available at:

7 Translating RCTs to Practice Randomized Controlled Trials Clinical Guidelines & Standard of Care 7

8 Necrotizing Enterocolitis (NEC) Randomized Controlled Trials Clinical Guidelines & Standard of Care 8

9 American Academy of Pediatrics 9

10 CHINA COLUMBIA SOUTH AFRICA 10

11 ISRAEL THAILAND TURKEY 11

12 Group Charge Recommendations about how to interpret literature when less than ideal studies Recommendations on the totality of the evidence needed to influence recommendations 12

13 Discussed regulations Agenda Reviewed potential mechanisms Discussed NEC Reviewed how physicians use literature Each member reviewed articles, in addition to statistician 18 total 10 in detail Summarized and discussed +/- 13

14 Why hasn t practice changed? Lack of a clear biologic mechanism Heterogeneity of interventions leads to caution in combining clinical trial results Probiotic strain Dose of probiotic strain How delivered, duration Patient population, ELBW vs. VLBW Measurement of outcomes (however, all cause mortality is +) Long term consequences have not been examined Phase IV trial Applicability of results to other populations Market barriers 14

15 Lack of a clear biologic mechanism 15

16 Do We Need a Mechanism? No NEC mechanism No mechanism for most of what we do in clinical medicine Lipitor, anti-arrhythmics, PPI, NSAIDs Mechanisms are important and we should continue to perfect but the NEC probiotic clinical literature is robust 16

17 Why hasn t practice changed? Lack of a clear biologic mechanism Heterogeneity of interventions leads to caution in combining clinical trial results Probiotic strain Dose of probiotic strain How delivered, duration Patient population, ELBW vs. VLBW Measurement of outcomes (however, all cause mortality is +) Long term consequences have not been examined Phase IV trial Applicability of results to other populations Market barriers 17

18 Heterogeneity of interventions Example Study Bin-Nun 2005 Costalos 2003 Dani 2002 Lin 2005 Samanta 2009 Intervention Probiotics group (N=72) received mixture of Lactobacillus bifidus, streptococcus thermophillus, and bifidobactrium infantis added to 3 ml of expressed breast milk or premature formula enteral feeds. Probiotics group (N=51) received preterm formula with added Saccharomyces boulardii 50mg/kg every 12 hours during the first week of life Probiotics group (N=295) received standard milk with Lactobacillus GG (Dicoflor,Dicofarm, Rome, Italy) with an added dose of colony forming units (cfu) once a day until discharge, starting with first feed. Probiotics group (N=180) received Infloran (L acidophilus and B infantis) obtained from the American Type Culture Collection in 1973, 125 mg/kg/dose twice daily with breast milk until discharge. The probiotic group received a probiotic mixture (Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 billion CFU) with expressed breast milk twice daily, the dosage being 125 g kg 1 till discharge. Soll RF. Probiotics: Are we ready for routine use? Pediatrics. 2010; 125:

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20 Heterogeneity of interventions Example Study Intervention Bin-Nun 2005 The incidence of NEC was reduced in the study group (4% vs 16.4%; P =.03) Death 3 in study group vs. 8 in control. Costalos 2003 Dani 2002 WE DIDN T DISCUSS No differences Lin 2005 Death incidence significantly lower in study group (9/180 vs 24/187). NEC (> stage 2) incidence significantly lower in study group (2/180 vs 10/187). Both significant. Samanta 2009 Death in active vs placebo 4 vs. 14, NEC 5 vs 15. Both significant. 20

21 Incidence rate ratios for a) all-cause mortality, b) non-fatal stroke, and c) non-fatal myocardial infarction in patients randomised to intensive glucose or standard control

22 Risk of Developing NEC with Probiotic Treatment

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25 Why hasn t practice changed? Lack of a clear biologic mechanism Heterogeneity of interventions leads to caution in combining clinical trial results Probiotic strain Dose of probiotic strain How delivered, duration Patient population, ELBW vs. VLBW Measurement of outcomes (however, all cause mortality is +) Long term consequences have not been examined Applicability of results to other populations Market barriers 25

26 Long Term Consequences Finally, long-term effects of this approach should be evaluated, as these organisms can alter immune responses and microbial epithelial cross talk, and therefore could result in many long-term effects. Indrio F and Neu J. The intestinal microbiome of infants the the use of probiotics. Curr Opin Pediatr April ; 23(2):

27 May 13 Baby Boy Judkins is a 34 1/7 week premature infant who has mild respiratory distress. Transferred to ICU in Saginaw, MI for prematurity. Placed in an incubator with oxygen therapy. Mother names her child Stevland ; the infant is eventually discharged. 27

28 Baby Boy Stevland Judkins suffers from retinopathy of prematurity. At that time, high level oxygen therapy was thought be helpful for premature infants. May 13, 1950 The side effect is abnormal blood vessel development in the eyes which leads to retinal detachment and blindness. Stevland turns out to be a talented musician. In 1961, he auditions with Barry Gordy at Motown. He later changes his name to Stevie Wonder 28

29 Why hasn t practice changed? Lack of a clear biologic mechanism Heterogeneity of interventions leads to caution in combining clinical trial results Probiotic strain Dose of probiotic strain How delivered, duration Patient population, ELBW vs. VLBW Measurement of outcomes (however, all cause mortality is +) Long term consequences have not been examined Applicability of results to other populations Market barriers 29

30 Applicability of Results Another point that makes the data problematic is that the combinations of probiotics used in the Lin et al. studies which are the most convincing for NEC prevention are not available in the United States. AAP Statement,

31 Why hasn t practice changed? Lack of a clear biologic mechanism Heterogeneity of interventions leads to caution in combining clinical trial results Probiotic strain Dose of probiotic strain How delivered, duration Patient population, ELBW vs. VLBW Measurement of outcomes (however, all cause mortality is +) Long term consequences have not been examined Applicability of results to other populations Market barriers 31

32 Market Issues Lack of a market champion Burden of regulation Lack of market/economic incentive Drug versus supplement Infrastructure for purchase, utilization in practice 32

33 Summary Translating research into practice is difficult Issues Need for basic science/clinical science translation Coordination of clinical trials (e.g., trial networks) Need for academic/industry partnerships Lessons learned from Probiotic NEC interventions may be instructive for other interventions (e.g., fecal microbiota transplant) 33

34 Evidence OBJECTIVES: To determine whether parachutes are effective in preventing major trauma related to gravitational challenge. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists. STUDY SELECTION: Studies showing the effects of using a parachute during free fall. MAIN OUTCOME MEASURE: Death or major trauma, defined as an injury severity score > 15. RESULTS: We were unable to identify any randomised controlled trials of parachute intervention. CONCLUSIONS: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

35 Number Needed to Treat Statins for MI for one year= Vitamin D for hip fractures=50 Antibiotics for sinusitis=15 Aspirin for CV protection=40 Imitrex for migraine=2.6 Probiotics for NEC=20