1. PrECIs (Pragmatic-Explanatory Continuum Indicators) “Spokes” Dave Sackett, on behalf of at least 23 collaborators

2. Why the smartass title? 1. We have to have an acronym to be in the same league as the cardiologists and many other trialists 2. PrECIs = precis (in both Canadian languages) = a summary or abstract of a longer text or speech.

3. The traditional distinction - 1 Some trials ask whether an intervention can work, under tightly- controlled, ideal conditions. Some trials ask whether an intervention can work, under tightly- controlled, ideal conditions. We call these “Explanatory” or “Efficacy” trials. We call these “Explanatory” or “Efficacy” trials.

4. Example of an Explanatory Trial “Among patients with angiographically- confirmed, symptomatic 70-99% stenosis of a carotid artery, can the addition of carotid endarterectomy (performed by an expert vascular or neurosurgeon with an excellent track record) to best medical therapy, vs. best medical therapy alone, reduce the risk of major or fatal stroke over the next two years of rigorous follow- up?” (NASCET: NEJM 1991;325:445-53) “Among patients with angiographically- confirmed, symptomatic 70-99% stenosis of a carotid artery, can the addition of carotid endarterectomy (performed by an expert vascular or neurosurgeon with an excellent track record) to best medical therapy, vs. best medical therapy alone, reduce the risk of major or fatal stroke over the next two years of rigorous follow- up?” (NASCET: NEJM 1991;325:445-53)

5. Example of an Explanatory Trial Eg, “Among highly compliant, high-risk hypertensive (DBP 115-129 mmHg) male US veterans, can 16-21 months of a fixed antihypertensive drug regimen (compared to placebo), closely monitored, reduce the risk of highly specific vascular events or their surrogates?” (US VA Trial Eg, “Among highly compliant, high-risk hypertensive (DBP 115-129 mmHg) male US veterans, can 16-21 months of a fixed antihypertensive drug regimen (compared to placebo), closely monitored, reduce the risk of highly specific vascular events or their surrogates?” (US VA Trial

6.  Advantage of an explanatory trial:  If negative, you can abandon the treatment (it won’t work anywhere)  Disadvantage of an explanatory trial:  If positive, you still don’t know whether it will work in usual health care conditions

7. The traditional distinction - 2 Other trials ask whether an intervention does work under the usual conditions that apply where it would be used. Other trials ask whether an intervention does work under the usual conditions that apply where it would be used. We call these “Pragmatic” or “Effectiveness” trials. We call these “Pragmatic” or “Effectiveness” trials. They are the primary focus of PraCTiHC and SUPPORT They are the primary focus of PraCTiHC and SUPPORT

8. Example of a Pragmatic Trial Among women at 12-32 weeks gestation whose clinicians thought they were at sufficient risk for pre-eclampsia or IUGR to be uncertain whether they should be prescribed ASA, does simply prescribing ASA (compared with placebo), and with no study follow-up visits, reduce the risk of a composite of bad outcomes for her or her baby? (CLASP: Lancet 1994;343:619-29)

9.  Advantage of a pragmatic trial:  If positive, it really works and you can implement the treatment just about everywhere  Disadvantage of a pragmatic trial:  If negative, you can’t distinguish a worthless treatment from an efficacious treatment that isn’t applied/accepted widely enough.

10. Because of these differences in interpretation and application... It is important to be able to distinguish Pragmatic from Explanatory trials

11. A UNC group developed a diagnostic test to distinguish them Identified 7 “domains” they thought were important. Identified 7 “domains” they thought were important. Asked each of 12 US & Canadian “Evidence-Based Practice Center” Directors to nominate 6 trials: Asked each of 12 US & Canadian “Evidence-Based Practice Center” Directors to nominate 6 trials: 4 to exemplify Pragmatic trials 4 to exemplify Pragmatic trials 2 to exemplify Explanatory trials 2 to exemplify Explanatory trials Two blinded raters applied the 7 domain- criteria and decided yes/no for each Two blinded raters applied the 7 domain- criteria and decided yes/no for each

12. Domain-criteria 1.Population was in primary care 2.Less stringent eligibility criteria 3.Health outcomes (function, QoL, mortality) 4.Long study duration; clinically relevant treatment modalities (considered compliance an outcome) 5.Assessment of adverse events 6.Adequate sample size to assess a minimally important difference from a patient perspective 7.ITT analysis

13. Results Kappa for yes/no on the domains = 0.42 Decided best cut-point for a positive test was the satisfaction of 6 of the 7 criteria Sensitivity = 72% Specificity = 83% LR+ 4.3 LR- 0.3

14. Their ROC Curve

15. But Pragmatic vs. Explanatory is not an either/or dichotomy Pragmatic vs. Explanatory is not an either/or dichotomy It is a continuum It is a continuum And individual methodological components of a trial often vary in their “pragmatic- ness” And individual methodological components of a trial often vary in their “pragmatic- ness”

16. And in SUPPORT we want to be able to describe BOTH Where a trial resides on that continuum … BOTH Where a trial resides on that continuum … AND Where a trial’s individual components reside on that continuum. AND Where a trial’s individual components reside on that continuum.

17. That is, we want a summary or “precis” of the trial and its individual methodological components

18. So a group of us have been working on: Pr = Pragmatic (to) E = Explanatory C = Continuum Is = Indicators

19. There are 8 PrECIs elements (“spokes”) Each is defined in terms of restrictions on an otherwise totally pragmatic trial Each is defined in terms of restrictions on an otherwise totally pragmatic trial The more restrictions in a trial, the higher its score, and the smaller the population to whom its results can be extrapolated The more restrictions in a trial, the higher its score, and the smaller the population to whom its results can be extrapolated

20. Spoke #1: Participant Eligibility Criteria The extent to which restrictive eligibility criteria were used in selecting study participants/patients The extent to which restrictive eligibility criteria were used in selecting study participants/patients Eg, age, risk, responsiveness, past compliance Eg, age, risk, responsiveness, past compliance

21. Spoke #2: Intervention Flexibility The extent to which restrictions were placed on how to apply the primary intervention and any co-interventions The extent to which restrictions were placed on how to apply the primary intervention and any co-interventions Eg, inflexible protocols for how every bit of the primary intervention was to be applied, and how many and which co-interventions were permitted Eg, inflexible protocols for how every bit of the primary intervention was to be applied, and how many and which co-interventions were permitted

22. Spoke #3: Practitioner Expertise The extent to which restrictive demands for ever-greater expertise were placed on the practitioners who applied the experimental maneuver. The extent to which restrictive demands for ever-greater expertise were placed on the practitioners who applied the experimental maneuver. Eg, experience, certification, recognition, validation of expertise through examination of past patients’ records Eg, experience, certification, recognition, validation of expertise through examination of past patients’ records

23. Spoke #4: Follow-Up Intensity The restriction of “usual” follow-up by demands for increasing frequency and intensity of follow-up of trial participants. The restriction of “usual” follow-up by demands for increasing frequency and intensity of follow-up of trial participants. Eg, more frequent follow-up, and attempts to track down and re-enlist trial participants who drop-out. Eg, more frequent follow-up, and attempts to track down and re-enlist trial participants who drop-out.

24. Spoke #5: Follow-Up Duration The restriction of follow-up duration so that it becomes too short to capture important health outcomes The restriction of follow-up duration so that it becomes too short to capture important health outcomes Eg, too short to capture long-term efficacy and safety, restriction to surrogate mechanistic “biomarkers” Eg, too short to capture long-term efficacy and safety, restriction to surrogate mechanistic “biomarkers”

25. Spoke #6: Participant Compliance Restrictions on leaving trial participants alone to follow/ not follow trial treatments as they would in usual health care. Restrictions on leaving trial participants alone to follow/ not follow trial treatments as they would in usual health care. Eg, compliance measurements, feed-back, and the employment of compliance- improving strategies. Eg, compliance measurements, feed-back, and the employment of compliance- improving strategies.

26. Spoke #7: Practitioner Adherence Restrictions on leaving trial practitioners alone to offer and apply trial treatments as they would in usual health care. Restrictions on leaving trial practitioners alone to offer and apply trial treatments as they would in usual health care. Eg, adherence measurements, feed-back, and the employment of adherence- improving strategies. Eg, adherence measurements, feed-back, and the employment of adherence- improving strategies.

27. Spoke #8: Primary Analysis Restrictions (in the form of exclusions) on the data that are incorporated in the primary analysis. Restrictions (in the form of exclusions) on the data that are incorporated in the primary analysis. Eg, excluding drop-outs or non-compliant patients from the primary analysis (“per protocol”). Eg, excluding drop-outs or non-compliant patients from the primary analysis (“per protocol”).

28. The results can be displayed graphically

29. The PrECIs Spokes

30. And the graphic form can be used to display agreement among readers/observers of the same trial report For example, the latest group of Trout Fellows read two low-dose aspirin trials for preventing/treating pre-eclampsia For example, the latest group of Trout Fellows read two low-dose aspirin trials for preventing/treating pre-eclampsia

31. The CLASP Trial (Lancet ’94)

32. The Caritis et al trial (NEJM ’98)

33. And the graphic form can be used to display an overall pattern in a trial

34. Could “connect the dots” of greatest agreement The resulting wheel could be informative The resulting wheel could be informative Small = applies to only a small proportion of the target population = Explanatory Small = applies to only a small proportion of the target population = Explanatory Large = applies to a large proportion of the target population = Pragmatic Large = applies to a large proportion of the target population = Pragmatic Lumpy-Bumpy = inconsistent/ ?confused protocol Lumpy-Bumpy = inconsistent/ ?confused protocol

35. A highly Explanatory “expert” surgical trial:

36. The CLASP Trial

37. The Caritis Trial

38. Can construct a consensus wheel

39. Might want a summary number Advantage: To give an overall indicator of “Pragmatic-ness” Advantage: To give an overall indicator of “Pragmatic-ness” Disadvantage: Hides individual spoke scores, which may have extreme values Disadvantage: Hides individual spoke scores, which may have extreme values Constructed in terms of “restrictions” to study participants, treatments, analyses, etc. Constructed in terms of “restrictions” to study participants, treatments, analyses, etc. Few restrictions = low # = Pragmatic Few restrictions = low # = Pragmatic Many restrictions = high # = Explanatory Many restrictions = high # = Explanatory

40. Summary number  Simply add the scores for the individual spokes

41. The NASCET trial scores 27 !

42. The Caritis Trial scores 10

43. The CLASP Trial scores 6

44. Progress to date 1.Have agreed on the 8 domains 2.Have developed 3 rd drafts of criteria for them 3.Have demonstrated moderate to good agreement in applying criteria

45. Work yet to be done: 1.Further refinement of the criteria for (at least some) spokes 2.Decide how they should be scored 3.Do more face-validation studies 4.Get observer agreement up to high levels

46. 1. Further develop the criteria for (some) spokes Do some individual elements need to be added, altered, or eliminated? Do some individual elements need to be added, altered, or eliminated?

47. 2. How should they be scored?....... Independent of each other, and equal in weight (1 point each, with their sum naturally limited to 4 points)? Independent of each other, and equal in weight (1 point each, with their sum naturally limited to 4 points)? Independent of each other, but weighted by their importance (1-4 points each, with their sum truncated at 4)? Independent of each other, but weighted by their importance (1-4 points each, with their sum truncated at 4)? Mutually exclusive, and progressive (maximum score of 4)? Mutually exclusive, and progressive (maximum score of 4)?

48. 3. More face-validation studies A comparison to the Gartlehner et al set of trials is underway A comparison to the Gartlehner et al set of trials is underway

49. 4. Get observer agreement up to high levels As part of our work in revising and improving the spokes and individual criteria As part of our work in revising and improving the spokes and individual criteria

50. Please help us ! 1.Please review the articles that Andy distributed ( Rodrigo Salinas & Eduardo Bergel) 2.Score them 3.Suggest improvements in the individual criteria 4.Suggest how they should be scored at every level (individual, spoke & overall)

51. Last week at the Trout Centre

53. Results of our PrECIs exercise Thanks, everyone !

54. Overall Ratings

55. How long (minutes) did it take to apply these PrECIs criteria? <10 x 10-14x 15-19xxxxxxxxx 20-24xxxxxxxx 25-29 30-34xxxxxxx 35-39x 40+xx

56. How difficult was it to apply these criteria? Very easy 1 2xx 2xx 3x 3x 4xxxx 4xxxx 5xxxxxxxxxx 5xxxxxxxxxx 6xx 6xx 7xxxxxx 7xxxxxx 8xxxxx 8xxxxx 9xx 9xx 10 10 Very Difficult

57. How well were important properties captured? Not at all 1 2 3xx 3xx 4xxx 4xxx 5xx 5xx 6xxx 6xxx 7xxxxxx 7xxxxxx 8xxxxxxxx 8xxxxxxxx 9xx 9xx 10xx 10xx Extremely well

58. How much fun did you have ? No fun at all 1x 1x 2x 2x 3x 3x 4xx 4xx 5xx 5xx 6xx 6xx 7xxxxx 7xxxxx 8xxxxxxxxxxx 8xxxxxxxxxxx 9xxx 9xxx 10x 10x Great fun

59. Observer Variation Results

60. Magpie Trial

61. Belfort Trial

62. Your suggestions for revisions Keep them coming!

63. Need to define when a Spoke might be “Not Applicable” Eg, Spoke 6: “Participant Compliance” Eg, Spoke 6: “Participant Compliance” When treatment is applied in a single session at the start of the trial (an operation, an immunization, etc.) participants can’t not comply. When treatment is applied in a single session at the start of the trial (an operation, an immunization, etc.) participants can’t not comply.

64. Further develop the criteria for Spoke 1: Participant Eligibility Criteria Don’t charge a restriction for a unisex disorder.

65. Further develop the criteria for Spoke 5: Follow-Up Duration 1.Spoke 5 really isn’t about follow-up duration, it’s about restrictions on the “events” chosen for the analysis. 2.So rename it and make it more clear

66. Further develop the criteria for Spoke 8: Primary Analysis Inclusions Need to distinguish between (or combine): Need to distinguish between (or combine): Drop-outs Drop-outs Non-compliant participants Non-compliant participants

67. Suggestions about scoring Make criteria within a spoke independent of each other, but weighted by their importance Make criteria within a spoke independent of each other, but weighted by their importance Could be worth 1-4 points for each restriction Could be worth 1-4 points for each restriction Maximum score for a spoke = > 4 Maximum score for a spoke = > 4

68. More face-validation studies A comparison to the Gartlehner et al set of trials is underway A comparison to the Gartlehner et al set of trials is underway

69. Improve observer agreement As part of our work in revising and improving the spokes and individual criteria As part of our work in revising and improving the spokes and individual criteria

70. Explore other issues How would PI ratings of their own trials compare with ours? How would PI ratings of their own trials compare with ours? Do trials with differing scores also have differing effect-sizes? Do trials with differing scores also have differing effect-sizes?

71. Results of our PrECIs exercise Thanks, everyone !

72. Logo Breakfast Club FernandoMarianEdgardo Anna Maria Kilgore