1. Implications for Clinical Trials
The Vioxx Debacle
Implications for Clinical Trials
Medical Grand Rounds March 3, 2005
Neil A Kurtzman, MD Grover Murray Professor University Distinguished Professor Texas Tech University Medical Center

2. Was there a valid medical reason for withdrawing Vioxx?
What is the safety profile of the COX-2 inhibitors?
What are the implications of this issue for clinical trials in general?

4. Why do we do clinical trials?
Safety and efficacy
Evidence based medicine
The law requires them
We must do them even when we know the result before the study is done

5. Consider ACE inhibitors and diabetic nephropathy
We knew ACE inhibitors were safe and efficacious for hypertension before they were used to treat diabetic nephropathy
So safety was not an issue, efficacy in treating diabetic nephropathy was

6. A 46 yo white type 1diabetic man was referred to me in 1990 by his ophthalmologist because of proteinuria – 1.5 g/day
He was hypertensive
Cr 1.2
He was blind
He was treated with ACEI and furosemide

7. His blood pressure was perfectly controlled
His blood sugar was always out of control
His proteinuria gradually (over a few years) disappeared – it’s now about 100mg/day
His Cr in 2005 is 1.2
A clinical trial is not necessary to prove that ACE inhibitors retard the progression of diabetic nephropathy because a scenario like the above was never seen before their use

8. Similar results have been seen in patients with Type 2 DM
Yet because clinical trials proving their efficacy (in Type 2 DM) had not been done it was felt justified to conduct trial comparing ARBs vs non-ACEI drugs in patients with proteinuria
Evidence Based Medicine was used to justify dubious studies

9. You don’t need a clinical trial to demonstrate the truly efficacious treatments
Morphine for pain
Diuretics for edema
Penicillin for syphilis
Insulin for DKA

10. What use are clinical trials?
They may detect small differences in treatments
Or no difference
The are necessary to detect effects that are far in the future
Prevention studies
They are very hard to do
The Vioxx debacle will make them even harder

11. A drug can be unsafe and non-efficacious X
It can be safe and non-efficacious X
Safe and efficacious X
Unsafe and efficacious * - thus a risk/benefit analysis is required

12. Clinical trials examining prevention are fraught with hazard
Consider a drug designed to prevent Alzheimer’s Disease
It would have to be given years before the disease would be detectable
Any such drug would have side effects
The side effects would be observed before any therapeutic effect could be seen

13. The drug might well be withdrawn before its beneficial effects could be noted
Suppose it caused a small but significant increase AMI, but totally prevented Alzheimer’s Disease
That would be a price worth paying, but we’d never find out because the trial would have been halted

14. When we prescribe a drug the question is not how safe is it compared to a placebo
It will always be less safe
But how safe compared to other treatments or to no treatment at all

15. The Purpose of Medicine
Prolong life
- prevent premature death
Relieve pain and suffering
What to do when treatment for one exacerbates the other?
Typically physicians focus on the first purpose while downplaying the second

16. NSAIDS lead to hospital admissions for ulcer complications in 0.25 - 1.6% of users per year
They cause at least 7000 deaths per year in the US
Celecoxib does not prevent ulcer complications (CLASS JAMA 284:1247, 2000)

17. VIGOR Study NEJM 343:1520,2000

18. Mortality rates were the same for Vioxx and naproxen (0.5 and 0.4%)
CV death rates were also identical (0.2%)
Ischemic CVAs were the same (0.2%)
AMI much less common in the naproxen group 0.1 vs 0.4%
RR 0.2 ( )

19. Merck withdrew Vioxx because of an increased rate of AMI in a colon polyp prevention study
The data from this study have just been published
Vioxx was compared to a placebo
Thus there could be no offsetting side effect that would mitigate any bad effect of Vioxx
Sugar pills don’t cause GI bleeding
Any positive therapeutic effect was years away
The increased AMI rate was seen after 18 months

20. CV Thrombotic Events in Controlled Clinical Trials of Rofecoxib
Circulation 104:2280, 2001
Includes the VIGOR Trial

23. COX-2 Selective NSAIDS and Risk of Serious CAD Lancet 360:1071, 2002
Retrospective study of about 300,00 0 TennCare patients
50 – 84 yo
Vioxx >25 mg/day more likely to have CAD
All user RR 1.70 NS (0.98 – 2.95)
New users 1.93 (1.09 – 3.42)
<25 mg/day no increase in risk 1.03 (0.76 – 1.37)
No cause and effect can be concluded

24. Selective COX-2 Inhibition and CV Disease Am Heart J 146:591, 2003

25. Concludes that there was not an excess of thrombotic CV events among patients taking Vioxx
Also concludes that naproxen likely has a cardioprotective effect

26. Risk of CV Event and Rofecoxib: Cumulative meta-analysis Lancet 364:2021, 2004

27. No mortality data – CV or otherwise
No risk/benefit analysis
Concludes that increased risk of AMI was evident from 2000 on
That CV toxicity was not dose dependent
That the VIGOR result were likely not due to a cardio-protective effect of naproxen
That the drug should have been removed from the market in 2000
And that it’s all Merck’s fault

28. Pages of critical mail appeared in the Lancet’s letters section
Meta-analysis is to analysis as metaphysics is to physics

29. Patients Exposed to Rofecoxib and Celecoxib Have Different Odds of Nonfatal MI Ann Int Med 142:157, 2005
Rofecoxib vs celecoxib OR 2.72 (CI, 1.24 – 5.95 Rofecoxib vs naproxen (1.37 – 8.40)

30. Selective COX-2 Inhibition and CV Effects Arch Int Med 165:181, 2005
Retrospective study Largely African-American High risk for CV disease

31. Also retrospective From Quebec
The Risk of MI with COX-2 Inhibitors: A Population Study of Elderly Patients Ann Int Med: In press
Also retrospective From Quebec

32. FDA Is Reviewing Information; Shares Tumble 11% on News
Pfizer Says Study Shows Heart Risk From Celebrex
FDA Is Reviewing Information; Shares Tumble 11% on News
By SCOTT HENSLEY Staff Reporter of THE WALL STREET JOURNAL December 19, 2004 6:34 p.m.
Pfizer Inc. said a government-sponsored study of its arthritis drug Celebrex in cancer prevention found a significant risk of cardiovascular problems, an unanticipated result that raises new questions about the safety of the popular drug.

33. CV Risk Associated with celecoxib in a Clinical Trial for Colorectal Prevention NEJM 2/23/05

34. CV Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention trial NEJM 2/23/05

35. NEJM Feb 23, 2005

37. Despite the title, no mortality data in the paper
Risk of AMI and sudden cardiac death in patients treated with COX 2 selective and non-selective NSAIDs: nested control study Lancet 365:475, 2005
Despite the title, no mortality data in the paper

38. Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery – NEJM 2/23/05
Increased CV events with these drugs after CABG
That the NEJM published this is a measure of the hysteria that surrounds this topic

39. The data show that:
Vioxx increases AMI
Vioxx doesn’t increase AMI
Celebrex does not increase the rate of AMI
Celebrex decreases AMI
Celebrex increases AMI
Naproxen protects against AMI
Naproxen does not protect against AMI
Naproxen is worse than Celebrex

40. If a drug that increases the rate of AMI is bad then a drug that reduces it must be good
Final Report of Aspirin Component of the Ongoing Physicians Health Study: NEJM 321:129, 1989
Double blind, randomized, placebo-controlled
Test the hypothesis that ASA in low doses reduces mortality from CV disease in healthy males

41. No effect on CV death rate
No effect on non CV death rate
No effect on total deaths
Marked decrease in both fatal and non fatal MI
Thus this study provides no evidence supporting ASA as primary prevention for CV mortality in healthy males

42. Warning Label for Adriamycin
Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3 to 5% at a dose of 400 mg/m², 5 to 8% at 450 mg/m² and 6 to 20% at 500 mg/m².* The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg/m². This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy or with pre-existing heart disease

43. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy.

44. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3 to 5% at a dose of 400 mg/m², 5 to 8% at 450 mg/m² and 6 to 20% at 500 mg/m²

45. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg/m². This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy or with pre-existing heart disease

46. Nobody has called for the removal of Adriamycin from the market
Cancer is obviously felt to be more important than pain
But is it?
I would ague that in many cases the reverse is true

47. Most people over 65 have DJD
Many of these patients have chronic pain that is disabling
These are the same patients that are at high risk for CV disease
Not treating this pain is not an option

48. What are the options?
Acetaminophen – effective in many patients, but not all
Must be given 3– 4 time/day
Breakthrough pain, especially at night is common
Some studies show it to be less effective than NSAIDs

49. Nonselective COX inhibitors
Effective
Serious GI complications common and sometimes fatal
Probably not a good drug to take every day for 20 years

50. COX-2 inhibitors
They are effective
Only Vioxx among these drugs available in the US has been shown to decrease adverse GI events
It’s off the market

51. Narcotics
Effective
But CNS effect makes their use problematic in elderly patients

52. Surgery and other invasive intervention common on a pain service
Often effective
Have their own risk profiles
Not every joint can be replaced or manipulated

53. Lancet 364:665, 2004

56. Lumiracoxib appears to have a better safety profile than the other COX-2 inhibitors
But is the FDA in a mood to approve another COX-2 inhibitor in the wake of the negative publicity generated by the Vioxx withdrawal?

57. The Purpose of Medicine
Prevent premature death
Relieve pain and suffering

58. What to do when these two goals conflict?
How much pain and suffering is worth how much of a reduction in life?
How much pain relief and reduced likelihood of GI bleeding is worth how many MIs in an elderly population?
No formula or set of practice guidelines will satisfactorily answer the question
Good judgment is the only answer

59. In my view the data thus far available doesn’t justify the removal of Vioxx
Merck made the decision based on liability consideration rather than on strict medical reasons

60. Implications for clinical trials
Many long term clinical trials are apt to be considered too risky by the drug companies
A drug that may prevent a disease that will not occur until far in the future may prove to have side effects before any therapeutic effect can be seen
This is particularly true if it is being compared to a placebo

61. The placebo will not have its own side effect profile that might offset those untoward effects of the study drug
Even if there are off setting effects the study drug may still be in trouble
Heart attacks seem to worry both the public and the profession more than GI bleeding
Hysterical reactions to side effects are more likely to be the rule rather than the exception

62. One of the country’s leading cardiologist’s said that “Any drug that causes heart attacks shouldn’t be on the market.”
Suppose it caused one AMI for every 100 cases of lung cancer that it cured
Any treatment requires a risk/benefit analysis

63. Merck May Return
Vioxx to Market
Move Depends on Whether
FDA Panel Decides Risks
Exist in Similar Medicines
By ANNA WILDE MATHEWS and SCOTT HENSLEY
Staff Reporters of THE WALL STREET JOURNAL
February 18, :30 p.m.

64. FDA Advisers Recommend
Return of Vioxx to U.S. Market
Shares of Merck Surge 13% on News
By ANNA WILDE MATHEWS
Staff Reporter of THE WALL STREET JOURNAL
February 18, :12 p.m.

65. Nothing is easier than to imagine that one has taken all relevant factors into account, when in reality there may be other factors which have influence, even if no data have been collected on them or they are not quantifiable. Where there are very significant differences in known factors between one group and another, it would be reckless to assume that all remaining unknown factors are the same.
Thomas Sowell

66. Think carefully before you prescribe
Evaluate clinical trials critically

67. 30

69. Celebrex Studies
Pfizer's announcement Friday stemmed from a trial conducted by the National Cancer Institute. The study, called the Adenoma Prevention with Celecoxib trial, involved patients taking high doses of Celebrex--400mg and 800mg daily -- to see if the drug could prevent colon cancer. The National Cancer Institute, which sponsored the study, stopped giving patients Celebrex after learning of the increased risk to patients during a review of the data. Recommended doses of Celebrex are 100mg to 200mg a day for osteoarthritis pain and swelling and 200mg to 400mg for rheumatoid arthritis symptoms, Pfizer said.
Pfizer also said this about a separate study: "In a separate long-term study, the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo. These findings are based on an identical analysis used to assess cardiovascular risk in the APC trial and conducted by the same independent safety review board. The information from this Pfizer sponsored trial was also received by Pfizer last night and, as with the APC information, was immediately shared by the company with the U.S. Food and Drug Administration."