1. Charting a middle road between the EBM movement, and Russo- Williamson Jeremy Howick Centre for Evidence-Based Medicine University of Oxford

2. Take home message 1The EBM movement are wrong to deny mechanistic reasoning any role in supporting efficacy (they have always recognized a role for mechanisms in generalizing). 2Russo and Williamson are incorrect that mechanistic reasoning is required to support the hypotheses about efficacy. 3The middle road: high-quality mechanistic reasoning can add evidential weight.

3. Comparative clinical studies versus mechanistic reasoning Black Box I Comparative clinical research O Mechanistic reasoning Reduce risk Serious arrhythmia Sudden Death Anti-arrhythmic drugs Reduce risk Sudden Death Anti-arrhythmic drugs Therefore

4. The EBM movement on mechanisms “[EBM] de-emphasizes clinical expertise and pathophysiologic rationale as sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research” Level Therapy 1aSR of RCTs 1bIndividual RCT 2aSR of cohort studies 2bIndividual cohort study 3aSR case-control studiIes 3bCase-Control Study 4Case-series 5Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles"

5. Russo and Williamson argue that mechanisms are necessary “To establish causal claims, scientists need the mutual support of mechanisms and dependencies”

6. Misplaced rationale for the Russo Williamson claim: The Semmelweis case

7. Sodium channels in the heart Block Risk  Heart’s action potential Block Electric impulse Slows Ventricular extra beats (VEBs) Risk  Ventricular fibrillation Sudden death Anti-arrhythmic drugs Mechanism for anti-arrhythmic drugs reduce the risk of sudden death Risk  More fine-grained mechanism for anti-arrhythmic drugs reduce the risk of sudden death Ventricular extra beats (VEBs) Anti-arrhythmic drugs

8. Other examples where mechanistic reasoning led us astray Anti-arrhythmic drugs to prevent sudden cardiac death. Babies to sleep on their front to reduce risk of SIDS HGH for hypercatabolism Oxygen for organ failure ERT for menopausal symptoms Radical mastectomy for breast cancer Rest for recovery Early screening for breast cancer …

9. Goiter Obstruction Respiratory function Radiotherapy inducesimpairs Goiter shrinks Evidence (from separate studies) Obstruction Respiratory function Radiotherapy induces impairs Goiter shrinks Mechanistic reasoning Mechanistic reasoning linking radiotherapy with improved respiratory function

10. High-quality mechanistic reasoning 1. All the links in the mechanism’s chain must be established as causal.

11. Reduce risk of by 90% Reduce risk of by 25%-50% Serious arrhythmia Sudden Death Anti-arrhythmic drugs Stochastic nature of mechanisms Sudden Death Anti-arrhythmic drugs Strength???

12. Paradoxical effects I2I2 I2I2 I I c3c3 c3c3 O O c c z3z3 z3z3 z z a a b3b3 b3b3 b b a3a3 a3a3 c2c2 c2c2 z2z2 z2z2 b2b2 b2b2 a2a2 a2a2 ¬O

13. Reduce risk of by 90% Serious arrhythmia Anti-arrhythmic drugs Increase risk of by 10% Serious arrhythmia

14. High-quality mechanistic reasoning All the links in the mechanism’s chain must be established as causal. The complexity and stochastic nature of mechanisms must be considered before drawing conclusions of the overall effect of the intervention on the clinically relevant outcome.

15. Why the 2 nd criterion is difficult to meet: the unknowns in biochemical mechanisms Pathways shown in blue represent the potentially beneficial effects of CETP inhibition, those shown in green may remain relatively unaffected, and those shown with dashed lines have potentially reduced activity after CETP inhibition.

16. Why the 2 nd criterion is unlikely to be met, cont’d. “It is still unknown, if methyl oxidation at ring B occurs before or after esterification with phytol” “In some microorganisms, cystathionine synthesis takes place via O-acetyl-L- homoserine” …

17. Summary Mechanisms are not always required, especially when the comparative clinical studies are well-conducted. Mechanisms are not always bad. High-quality mechanistic reasoning can, and should, be used as evidence.

18. Other roles for mechanisms Generalizability? Hypothesis generation? Explanation? Convincing people? The quality criteria apply here too!

19. Other potential roles for mechanisms: Generalizing the results of studies This is a different problem than the one I was talking about. Generalizability is a real problem (selected population, rarified circumstances…) The same applies to mechanisms (as we saw yesterday in Carl’s talk). Waving a wand and saying ‘mechanism’ doesn’t solve the problem. We need to trace a causal pathway in the individual, and engage in high-quality mechanistic reasoning. Mechanisms are not the only way to generalize…

20. Thank you Questions welcome now or email: jeremy.howick@dphpc.ox.ac.uk

21. How to combine mechanistic evidence with comparative clinical studies (a sketch for Lindsay) Just as comparative clinical studies must reach a certain threshold of quality in order to be useful, so must mechanistic reasoning. All evidence that reaches its respective quality threshold is sufficient to add evidential weight. There is no need to get more specific than that.

22. How to generalize without mechanisms We cannot sample from the target population. But no need to exclude 60%-90% of potentially eligible participants from trials. We can make our exclusion criteria inclusive. This will increase the variability and hence the size and cost of the trial. But this is a cost that is well worth paying.

23. Role 2: Persuasion “The history of medicine presents many cases in which causal claims made solely on the basis of statistics have been rejected until backed by mechanistic … knowledge” This is true (Semmelweis, Warren and Marshall). “It is true that Kuhn’s ideas give a rather convincing explanation of Semmelweis’s failure, but it is important to remember that such an explanation is not a justification.”

24. Role 3: Mechanisms for hypothesis generation It is true that many of our hypotheses are generated by the basic sciences. But are these efficient ways of generating hypotheses?

25. The exaggerated stability of mechanisms “entities and activities organized such that they are productive of regular changes from start or set-up to finish or termination conditions” (MDC) “invariant, change-relating generalizations” (Glennan). “… the existence of a mechanism provides evidence of the stability of a causal relationship” (Russo and Williamson)

26. Basic science is not necessarily an efficient way to generate hypotheses A study examined 101 major ‘mechanistic’ findings in the top basic science journals [INSERT THESE IN TALK] Science, Nature, Cell, Journal of Experimental Medicine, Journal of Clinical Investigation, and the Journal of Biological Chemistry between 1979 and 1983. By 2002, 27 (25%) of the allegedly promising technologies had been clinically 19 (20%) indicated a ‘positive’ benefit 5 (5%) have been approved for marketing 1 (1%) has a clinically relevant outcome There are other ways of generating hypotheses – Chicken soup for the common cold