pharmacovigilantism and avandia

8/13/2019 Pharmacovigilantism and Avandia

1/37

1

Pharmacovigilantism and Avandia

Nathan A. SchachtmanMcCarter & English LLP

Philadelphia, PA

[email protected]


2/37

2

Falsehood flies and the truth comes limping

after;so that when men come to be undeceived it istoo late:

the jest is over and the tale has had its effect.

Swift, T h e E x a m i n e r , Number 15 (November 9, 1710). In: Ellis FH,ed. S w i ft v s M a i n w a r in g : t h e E x a m i n e r a n d t h e M e d le y . Oxford,England: Clarendon Press, 1985:19-26.


3/37

3

Selikoff Asbestos Flying - 1966


4/37

4

Asbestos Gastrointestinal Cancer Insufficient Evidence

Institute of MedicineCommittee on Asbestos:

Selected Cancers (2006)1966 2006 (40 Years Later, Limping)


5/37

5

Silicone Gel Falsehoods Bleeding

Through


6/37

6

Silicone Gel Falsehoods Enhanced


7/37

7

Silicone Gel Truth Bleeding

Through


8/37

8

PPA Falsehoods Congested

FDA Hearing: Oct 19, 2000; Study published online 11/9/2000


9/37

9

PPA Truth Decongested

"I mean, you could almost say that there was someunethical activity with that Yale Study. It's real close. Imean, I -- I am very, very concerned at the integrity ofthose researchers."

p.46

"Yale gets -- Yale gets a big black eye on this."p.47

O'Neill v. Novartis AG , California Superior Court, Los Angeles Cty., Oral Argument on Post-Trial Motions,March 18, 2004 (Hon. Anthony J. Mohr)


10/37

10

Hormone Therapy Falsehoods

Flashing HotMay 31, 2002 WHI RCT Stopped

July 17, 2002 JAMA- Express PublicationReported increased risks of breast cancer,heart attack

Little explanation or justification for therandomization of women, avg. age = 63+,for a study of post-menopausal meds


11/37

11

WHI 2006No

IncreasedRisk ofBreastCancer

within RCT

Anderson, et al., "Priorhormone therapy and breast

cancer risk in the WHIrandomized trial of estrogenplus progestin," 55 Maturitas

103 (2006)


12/37

12

Junk Science?

Respected scientists

Peer-reviewed studies

Respected journalsPlausible, coherent theories

Some supportive evidence Science is facts. Just as houses are made of stones, so is sciencemade of facts. But a pile of stones is not a house and a collection offacts is not necessarily science. Jules Henri Poincare (18541912)


13/37

13

Abridgement of the Scientific

ProcessDriven by media, special interest groupsUrgency for immediate answers

Legal system Regulatory system Patients, physicians

Driven by careerism among scientists The rewards of scientific discovery Grants, promotions, recognition


14/37

14

Desire to Wear a White Hat

It was sort of the in thing to exaggerate . . .[because] that would be good for theenvironmental movement.*** At the time it looked like you were wearing awhite hat if you made these wild estimates.

- Philip Enterline, quoted in Reynolds, Asbestos-Linked CancerRates Up Less Than Predicted. J. Natl Cancer Inst. 84:560(April 15, 1992)


15/37

15

Avandia -- Rosiglitazone

Falsehoods Flying?


16/37

16

The Diabetic Patient Population

Mitka, "Report Quantifies Diabetes Complications," 297 JAMA 2337 (2007)


17/37

17

Limited Therapeutic Options

Non-pharmaceutical: Exercise/diet

Sulfonylureas limited durability, hypoglycemiaMetformin contraindicated in patients with liverand kidney diseaseInsulin patient resistance, non-compliance

All serious medications for serious, deadlydisease


18/37

18

Nissen & Wolski 2007

Meta- or Shmeta-Analysis?Submitted to the NEJM on May 1, 2007Published on-line at the NEJM website onMay 21, 2007Time, mature reflection, peer-review, andscientific judgment were abridged

Why?


19/37

19

Exclusion of Zero-Event Trials in

Nissens WorkContrary to the editorials, 42 trials werenot pooled for any particular outcome

Only 22 of the 48 available Glaxo trialswere combined for cardiovascular deaths(over 50% of studies excluded)

Only 38 of the 48 available Glaxo trialswere combined for heart attacks


20/37

20

Exclusion of Zero-Event TrialsBiased Nissens Study

[T]he exclusion of zero total event trials frommeta-analyses increases the effect size comparedto meta-analyses that include these trials.

Zero-event trials provide relevant data byshowing that event rates for both the interventionand control groups are low and relatively equal.

Friedrich, et al., Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all

available data, 7 B M C M e d R e s e a rc h M e t h o d o lo g y 5 (2007)


21/37

21

Failure to Provide Appropriate Sensit ivity Analyses

Sensitivity analyses (what ifs) need to be performed to

test study inclusion/exclusion decisions such as theexclusion of zero-event studies

Critical need to test assumptions in meta-analyseswidely acknowledged in the field:

Good meta-analyses aim for complete coverage of allrelevant studies, look for the presence of heterogeneity, andexplore the robustness of the main findings using sensitivityanalysis.

In meta-analyses without sensitivity analyses the reader hasto make guesses about the likely impact of these importantfactors on the key findings.

Davies & Crombie, What is meta-analysis? Hayward Med. CommunicationsReport 2001 http://www.evidence-based-

medicine.co.uk/ebmfiles/WhatisMetaAn.pdf


22/37

22

Nissens Study Lacked Patient-Level

DataPaper presented odds ratios, not hazardratios

No time-to-event analyses

No central adjudication of outcome ofinterest (M.I. or cardiovascular death)


23/37

23

The Nemesis of Meta-Analysis:Heterogeneity

Statistical vs. clinical heterogeneityPatients - with and without diabetes

Avandia vs. other monotherapy Avandia vs. insulin Avandia and another drug vs. other dualtherapy

Dosages (2 mg., 4 mg., 8 mg. Avandia) vs.variable doses of comparator drugDifferent definitions & measures of harm

See Fletcher, What is heterogeneity and is it important? 334 B.M.J. 94 (2007)


24/37

24

Heterogeneity of Comparisons with Rosiglitazone

Comparisons to any active comparator are dangerous forassessing safety;

Insulin comparator studies drive Nissens results

Placebo controlled trials are the only pure test for safety

Placebo-controlled trials are unethical for a populationwith disease


25/37

25

The Inclusion of Active Comparator Drug Trials:Metformin Studies

Three of the 42 trials (including 4,200 patient ADOPT)evaluated Avandia in isolation against Metformin.

Metformin may well reduce cardiovascular morbidity:

Johnson, et al., Reduced cardiovascular morbidi ty and mortality associated withmetformin use in subjects wi th Type 2 diabetes. 22 Diabet. Med. 497 (2005)

Carlsen, et al., Metformin improves blood l ipid pattern in nondiabetic patientswith coronary heart disease. 239 Intern. Med. 227 (1996);

Yang & Holman, Long-term metformin treatment s timulates cardiomyocyteglucose transport through an AMP-activated protein k inase-dependent reductionin GLUT4 endocytosis. 147 Endocrinology 2728 (2006);

Libby, Metformin and vascular protection: a cardiologist' s view. 29 DiabetesMetab. 6S117 (2003).


26/37

26

The Inclusion of Active Comparator Drug (Insulin) in theTrials

5 of 42 trials evaluated Avandia combined with insulinagainst insulin alone.

Treatment arm received lower doses of (cardio-

protective) insulin

Insulin comparator studies drive Nissens results(OR point estimates of 2.8 and 5.4 for MI and CVD death)

As with Metformin, insulin has been shown to reduce CVD morbidity.

Care must be taken with the inclusion and interpretationof these studies.


27/37

27

The Inclusion of Active Comparator Drug TrialsInsulin Studies (contd)

Stehr, et al., Insulin effects on myocardial func tion and b ioenergeticsin L-bupivacaine toxici ty in the isolated rat heart, 24 Eur. J.

Anaesthesiol. 340 (2007) Fauconnier, et al., Insulin potentiates TRPC3-mediated cation currents

in normal but not in insulin-resistant mouse cardiomyocytes, 73Cardiovasc. Res. 376 (2007);

Ma, et al., Vasculoprotective effect of insulin in theischemic/reperfused canine heart: role of Akt-stimulated NOproduction, 69 Cardiovasc. Res. 57 (2006);

Gu, Antiapoptotic mechanism of insul in in reoxygenation-inducedinjury in cultured cardiomyocytes of neonatal rats, 25 J. HuazhongUniv. Sci. Technolog. Med. Sci. 632 (2005).


28/37

28

Table 5. Risk of Myocardial Infarction and Death from Cardiovascular Causes

for Patients Receiving Rosiglitazone versus Several Comparator Drugs.Comparator Drug Odds Ratio

(95% CI) p Value

Myocardial infarction Metformin 1.14 (0.701.86) 0.59

Sulfonylurea 1.24 (0.781.98) 0.36

Insulin 2.78 (0.5813.3) 0.20

Placebo 1.80 (0.95-3.39) 0.07

Combined comparator drugs 1.43 (1.031.98) 0.03

Death from cardiovascular causes Metformin 1.13 (0.343.71) 0.84

Sulfonylurea 1.42 (0.603.33) 0.43

Insulin 5.37 (0.5156.52) 0.16

Placebo 1.22 (0.642.34) 0.55

Combined comparator drugs 1.64 (0.982.74) 0.06

Nissen & Wolksi 2007 A Very Fragile Meta-analysis of Avandia


29/37

29

The Editorialists

Drazen, Nathan, PsatyRender their judgments about safety withoutany real consideration of efficacyIgnore clinical needs of patients and theirphysiciansFail to deal with clinical heterogeneity

Advance a faulty notion of powerDisparage study of oral anti-diabetic in pre-diabetic population as largely marketingquestionsSensationalize to advance their political agenda


30/37

30

What is the measure of regulatory

success? The primary measure of regulatorysuccess is the timeliness of information,

warnings, and withdrawals.Psaty & Furburg, at

The timeliness of safe, efficacious drugscoming to market?


31/37

31

Observational Studies Needed to

Address IssuesClinical trials can not always deal with howmedications are used in the real world

Clinical trials will not always answer theexact safety question posed by adverseeventsLimited duration of trials may limit powerand understanding of time course ofsafety and efficacy issues


32/37

32

Insulin Sensitizing Pharmacotherapy for Prevention of M.I. in Patients With DM


33/37

33

Observational Studies


34/37

34

Large propensity-matched cohort


35/37

35

Specific Causation Problems

All patients by definition will have had riskfactors for coronary heart disease

If there should be any risk, the relativerisk is smallNo sequestered higher risks (> 2.0) inmeaningful subgroups


36/37

36

Risk Cause"Knowledge that a factor is associated withincreased risk of disease does not translate into thepremise that a case of disease will be prevented if aspecific individual eliminates exposure to that riskfactor.

* * *

Disease pathogenesis at the individual level isextremely complex."

Graham Colditz, "From epidemiology to cancer prevention: implications for the21st century," 18 Cancer Causes Control 117, 118a (2007)


37/37

37

Look Before You Leap

Plaintiff patient population is all at risk for CVDCausation (general & specific) quagmirePrescribers will resent political-, litigation-

driven attack on an important medicine in theirarmentariumThe medication remains licensed, and FDA &DSMB continue to approve the ongoing trials

The bloom will come off the Nissen rose. Smokey, youre entering a world of pain.

pharmacovigilantism and avandia

Documents