Control Groups in Clinical Trials

1. Control Groups in Clinical Trials

2. Control Group: Definition The reference group or standard treatment against which a new treatment is compared The basis for comparison in a clinical trial Anchor for comparison

3. Types of Controls Concurrent Randomized Placebo No treatment Dose response Active Single treatment Choice of treatments Optimized management Usual care Non-Randomized Historical (e.g., patient registry) Combination of randomized and non-randomized (concurrent or historical)

4. Meinert gives the following requirements for experimental and control treatments: Must be distinguishable Medically justifiable Ethically OK Both must be acceptable to patients and investigators Reasonable doubt concerning efficacy Should be reason to believe benefits outweigh risks Method of administration should be as similar as possible to real-world use

5. Placebos Placebo (def.) - A medication prescribed more for the mental relief of the patient than for its actual effect on the disorder; something tending to soothe - Webster�s Dictionary A pharmacologically inactive agent to maintain blinding in a clinical trial (no specific action on the patient�s symptoms or disease)

6. Angina Pectorisand the Placebo Effect (Benson, H., NEJM, 1979) Subjective improvement for five 82.4 � 9.7%inactive treatments used prior to1960 (13 studies, 1187 patients)

7. Treatment of Mild Hypertension Trial Selected self-reported side-effects (placebo versus active treatment) Weakness 18% versus 16% Headaches 34% versus 22% Muscle pain 33% versus 26%

8. Example After 2nd day of treatment: Cured/ Cured Improved Antihistamine 13.4% 68.2%

9. Second Day of Treatment: Cured/ Cured Improved Antihistamine 13.4% 68.2% Placebo 13.9% 64.7%

10. 1) Suggestion (placebo effect) 2) Changes in course of disease

11. Placebo Effect Subjective changes as well as objective physiological changes (beneficial and toxic) produced by placebo (not limited to psychological responses)

12. Can the Placebo be the Cure?Science, April 9, 1999 �Merck was struck by the curse of the placebo effect�patients who had received a dummy pill had done unexpectedly well. �it highlights a chronic problem for psychopharmacology � the placebo effect�

13. Example of Impact of Placebo Responderson Results of a Trial A Crossover Experiment of Four Treatments

14. Reference: Jellinek, Biometrics Bulletin A = a + b + c B = a + c C = a + b D = placebo Response variable = fraction of headaches relieved A 0.84 B 0.80 C 0.80 D 0.52

15. A Comparison of Response to Treatments A, B and C by the Response to D (Placebo) A 0.82 B 0.87 C 0.82 120/199 Subjects

16. A 0.88 B 0.67 C 0.77 79/199 Subjects

17. Placebo Effect Summary 1. Placebos can be very effective particularly as judged by subjective response variables 2. Placebos control both for suggestion and spontaneous changes in course of disease � usually difficult to disentangle 3. Removal of �placebo responders� before randomization (more later on this) May make it easier to detect treatment differences; and Alters questions being asked

18. Considerations in Using aNo Treatment/Placebo Control No standard therapy with established efficacy Cost/availability of standard therapy Size/clarity of results Toxicity of test treatment Risk to patients Informed consent

19. Considerations for Use of Placebo Controls

20. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Advantages of placebo-controlled trials Ability to demonstrate efficacy credibly Measures �absolute� effectiveness and safety Efficiency Minimizes effect of subject and investigator expectations

21. Controversial Issues Concerning Use of Placebos Short-term studies of treatments with known long-term benefits, e.g., what is short-term? how much risk is tolerable? Withdrawal of active treatment and random assignment to new drug or placebo, e.g., psychiatric trials Definition of �standard of care� varies from country to country.

22. Perinatal Transmission of HIV PACTG 076 established that efficacy of zidovudine (AZT) in preventing transmission from mother to child (67.5% relative reduction) AZT � antepartum (oral), intrapartum (IV), plus AZT for newborn Are placebo controlled trials of simpler, less costly regimens in other countries ethical?

23. In many active controlled trials, placebos are used to facilitate blinding. New Treatment + Optimal Medical Management versus Placebo for New Treatment + Optimal Medical Management

24. Treatment of Mild Hypertension Study (TOMHS) Weight Loss + Na Reduction + Alcohol Reduction and

25. Placebos Are Also Used In Active Controlled Studies for Blinding A = slow release A = conventional tablet (200 mg) (100 mg) B = placebo B = conventional tablet (100 mg)

26. �Add On� Study AZT AZT + + 3TC vs. 3TC + + Indinavir Placebo Hammer et al., NEJM 1997; 337:725-33.

27. Randomized Discontinuation Design Withdraw vs. Continue BP Meds BP Meds (Placebo) + + Nutrition Nutrition Advice Advice

28. �Take Away� Studies

30. CONVINCE Clinical Trial

31. Optimal Medical Care (or Management) Control

32. Multiple Risk Factor Intervention Trial(MRFIT)

33. In MRFIT �Usual Care� Was Pretty Good! ? DBP (mm Hg) -10.5 -7.4 ? cholesterol (mg/dl) -12.3 -6.4 % quitting smoking 46 29

34. MRFIT Illustrates Challenges Defining�Usual Care� Tension between control over experimental conditions versus relevance to clinical care � how strictly should control treatment be specified? (explanatory versus pragmatic approach) Best practices may be under-utilized in the �real-world� Evidence base to guide usual care may not be optimal and may change over a long-term study.

35. One of Muench�s Postulate �Nothing improves the performance of therapy like the weakness of controls in its appraisal.�

36. Low Dose vs. Intermediate Dose vs. High Dose vs. Placebo Dose Comparison/Escalation

37. Cannot compare dose levels from a trial designed to compare two forms of management. If dose is determined by response of patient, then responses of patients at different dose levels cannot be compared. Circular Motion(Bradford Hill)

38. Cox-2 Inhibitor Studies VIGOR � rofecoxib (Vioxx) versus naproxen APPROVe � rofecoxib (Vioxx) versus placebo MEDAL � etoricoxib versus diclofenac (should the comparator have been naproxen?)

39. Often Cited Reasonsfor Uncontrolled Studies 1. Unnecessary for large effects 2. Controlled studies are more difficult to implement 3. Availability of patients 4. Ethical reasons� no control treatment available� untreated patients at high risk of death or serious illness 5. Historical data for comparison is available

40. Historical Controls Could Result in An Effective Treatment Being Abandoned: REMATCH Trial in Advanced HF Design assumptions 75% 50% Results of trial 92% 77% Source: NEJM, 2001 15:1435-1443.

41. SummaryConsiderations in Choice of Experimental and Control Treatments Acceptability by patients and clinicians Indifference/doubt concerning relative efficacy/safety Some basis for thinking that there could be a difference of clinical/public health importance Timing is everything!