Comparative Efficacy Gordon Schiff MD Cook County (Stroger) Hospital with Jay Duhig UIC College of...
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Transcript of Comparative Efficacy Gordon Schiff MD Cook County (Stroger) Hospital with Jay Duhig UIC College of...
Comparative Efficacy
Gordon Schiff MD Cook County (Stroger) Hospital
with Jay Duhig UIC College of Pharmacy
Monday March 12th 2007
Ray W and Stein C. N Engl J Med 2006;354:194-201
Principal Limitations of the Present Drug-Regulation ProcessComparative (or relative) Efficacy— a Leading Issue for Drug Policy Reform
Lyrica Meeting w/ Drug Rep
Response
Evidence for Drug Efficacy Requires Comparisons
• Not enough to say “patients responds” to a drug
Evidence for Drug Efficacy Requires Comparisons
• Not enough to say “patients respond” to a drug• 3 concepts, and related trial designs essential for
understanding efficacy
FRAMEWORK- 3 KEY PARADIGMS• Placebo controlled RCT – Does it work?• Comparative efficacy trails – Does it work better
than other altenatives (drug, nondrug)? • N of 1 trials – Does it work in this patient?
Response
Vs. Placebo
Comparison I: Placebo
• Placebo controlled RCT– 1st RCT was MRC Streptomycin 1948
• Need for concurrent randomized controlled groups• Interesting debates over ethics of with-holding streptomycin
to controls– With-holding drug “proven to work” in animals
– Only resolved by historical twist of drug shortage
» Reserved small quantity that was available for TB meningitis and miliary TB
– 1st Origins of placebo controlled trail • Beecher placebo trials
Vs.
I. Other Drugs
II.Same Class Drugs
III.Non Drug Rx
Comparison II: Other Treatments
1. Compare w/ other classes of drugs
2. Compare w/ other drugs in same class
3. Compare w/with non-drug alternatives
vs.
Comparison III: N of 1 Trials
• For later discussion
Copyright ©2003 BMJ Publishing Group Ltd.
MacGillivray, S. et al. BMJ 2003;326:1014
Meta-analyisis: SSRI vs. tricyclic antidepressants
MacGillivray, S. et al. BMJ 2003;326:1014
Comparative Efficacy Azithromycin for Otitis
Comparative Efficacy Azithromycin for Pharyngitis
Comparative Efficacy Azithromycin for Acute Sinusitus
2/2007 Am J Resp Clinical Care Med
“Comparative efficacy” (and purpose) ……of two types of trials
• Studies asking how good is my drug?– Studies for manufacturer R&D and selling a drug– Starting point is the company well-being– Bias towards showing the value of the drug
• Placebo is usually comparator that shows biggest benefit
– Constitutes majority of drug trials today• Drug industry budget vs. NIH
• Studies asking what is the best therapy?– Fundamentally about comparative efficacy– Starting point is a given problem and patient well-being– Tend to be more complex and harder to perform– Relatively fewer studies of this type– Although what is most needed, growing disproportionately fewer
Venues for Evaluation of Patient Oriented Comparative Efficacy
Existing national effortsNICE --National Institute for Health and Clinical Excellence
CDAC --Canadian Drug Advisory Committee
PBAC - Pharmaceutical Benefits Advisory Committee
Publicly accountableLooking at cost in addition to
efficacy/safetyDrug bulletins, evaluations
Prescrire Cohchrane
Local Formularies
NICE
• UK- National Institute for Health & Clinical Excellence
• Independent organization producing– Public health guidelines– Treatment guidelines– Clinical guidelines
• Published appraisals– http://www.nice.org.uk/guidance/TA/published
2006: w572-w585
Copyright restrictions may apply.
Topol, E. J. JAMA 2004;0:293.3.366-368.
Event Rates of Cardiovascular Death, Myocardial Infarction, and Stroke in the Adenoma Prevention With Celecoxib (APC) Trial
Three myocardial infarctions, all inthe rofecoxib group, were not included in thedata submitted to the Journal. The editors firstbecame aware of the additional myocardial infarctionsin 2001 when updated data were madepublic by the Food and Drug Administration.Until the end of November 2005, we believedthat these were late events that were not knownto the authors in time to be included in the articlepublished in the Journal on November 23, 2000.
NEJM 12/29/2005
It now appears, however, from a memorandumdated July 5, 2000, that was obtained by subpoenain the Vioxx litigation and made available tothe Journal, that at least two of the authors knewabout the three additional myocardial infarctionsat least two weeks before the authors submittedthe first of two revisions and 4 1/2 months beforepublication of the article. Given this memorandum,it appears that there was ample time to includethe data on these three additional infarctionsin the article.
The fact that these three myocardial infarctionswere not included made certain calculationsand conclusions in the article incorrect. Althoughonly summary percentages, not actual numbersof myocardial infarctions, were included in theJournal article, the following tables display thenumerical data without (Table 1) and with (Table2) the three myocardial infarctions.Lack of inclusion of the three events resultedin an understatement of the difference in risk ofmyocardial infarction between the rofecoxib andnaproxen groups (presented in the article as areduction in the risk with naproxen but shownhere as an increase in the risk with rofecoxib).
It contained other data on cardiovascular adverseevents that we believe would have been relevantto the article. We determined from a computerdiskette that some of these data were deleted fromthe VIGOR manuscript two days before it was initiallysubmitted to the Journal on May 18, 2000.Taken together, these inaccuracies and deletionscall into question the integrity of the dataon adverse cardiovascular events in this article.We have asked the authors to submit a correctionto the Journal.
NEJM 12/29/2005
Curfman NEJM 3/16/06
Curfman NEJM 3/16/06
U.S. Deaths from Vioxx More than Vietnam War
• 1/1999--9/2004: 106.7 million rofecoxib prescriptions in US– 17·6% were high-dose, mostly to older patients
• In 2 Merck-sponsored randomised trials: 2,25 relative risks for AMI– 5x for high-dose rofecoxib and 2x for the standard dose – Background rate AMI control NSAID users varied from 7·9 per 1000
person-years in CLASS1 to 12·4 per 1000 person-years in TennCare.
• Using Merck studies relative risks w/ these background rates 88,000– 140,000 excess cases serious coronary disease in US
• Using US national case-fatality rate-44%,suggests thousands of deaths attributable to rofecoxib use (~38,000-61,000)
Graham Lancet 2005
The term “innovation” covers 3 concepts :
- the commercial concept
- the technological concept
- the concept of therapeutic advance
A clear difference between:
• newly marketed substance, or indication, or formulation, etc.
• industrial innovation (chemistry, biotechnology)
• therapeutic advance : « a new treatment that benefits the patient when compared to existing options »– (ISDB Declaration) -
ISDB Declaration on therapeutic advance in the use of medicines (November 2001)
The 3 components of therapeutic advance
1- efficacy
2- safety
3- convenience
Prescrire’s rating system
BRAVOThe drug is a major therapeutic advance in an area where previously no treatment was available
A REAL ADVANCEThe drug is an important therapeutic innovation but has certain limitations
Prescrire’s rating system
OFFERS AN ADVANTAGEThe drug has some value but does not fundamentally change the present therapeutic practice
POSSIBLY HELPFULThe drug has minimal additional value, and should not change prescribing habits except in rare circumstances
Prescrire’s rating system
NOTHING NEWThe drug may be a new substance but is superfluous because it does not add to the clinical possibilities offered by already available treatments
NOT ACCEPTABLEDrug without evident benefit but with potential or real disadvantages
Prescrire’s rating system
JUDGEMENT RESERVEDThe editors postpone their judgement until better data and a more thorough evaluation of the drug are available
23 Years Ratings New Drug “Advances” by Prescrire (1981-2003)
Rating # %Bravo 7 0.2%
A real advance 77 2.7%Offers an advantage 217 7.6%
Possibly helpful 455 15.8%Nothing new 1,913 66.6%
Not acceptable 80 2.8%Judgment reserved 122 4.2%
Total 2,871 100
Comparative Efficacy Does it work compared to nothing
Comparative Efficacy
Does it work: compared to something else
Is it better, how much?
CE is important
• U.S. drug spending is very highXX – Increasing at XX%/year
• How much is spent on new drugs on patent ??– Is this worth it are they better?
– Majority is drug costs– Waste of tax-payer money
• Me-too drugs are the dominant trend– Artificial distinctions– Drug companies like creating a niche (based on packaging dosing)– Be cautious of sub-group analysis and making false
comparison/claims
• CE studies are in the best interest of patients• Other countries have regulatory agencies to provide CE
information
Choices in Exam Room
– Inviduciaula decisionmaking – What should be happening
• Succumbing to marketing the pathof least resistance• Succumbing to the easy solution offered by the drug rep• Weighing pros and cons of the from literature and
assessmewnt of the patients specific risk and benfits• Potential for a real evidence based way to decide if that drug
is benefiting patient and best choice \– N of 1
US FDA
• Very definition of requirements for approval and review – comparative efficacy isn’t on the table – get a qoute from law
• What does IOM say about CE harvest qoutes and references
• Follow up on the article of doctors not following guideilnes
Common Drug Review(CDC)
• Canadian Agency for Drugs and Technology in Health (CADTH)
• Goals:– How does it compare with alternatives?– Which patients will it benefit?– Will it deliver value for money?
Screenshot of clinical guidelines for hypertension - flowchart
Australia’s ExamplePharmacy Benefit Scheme
FDA
• What does the FDA offer to clinicians
• Drug approval letter
• Medwatch safety information
• Ahrq– Brief story re back surgery– Has the potential to fill this role– Mandates of the certs??
Compare sources on LYrica
What does the drug industry think about CE studies?
• Highly subjective
• Advocates just want to spend less
• Requiring CE trials will slow down delivery of new drugs to patients
Sources
• http://www.cadth.ca/media/cdr/complete/cdr_complete_Lyrica_Jan26-06.pdf
• Compare 2 forms of drug information provided by drug regulatory agencies– http://www.ti.ubc.ca/pages/letter61.htm– http://www.fda.gov/cder/foi/appletter/2004/217
23ltr.pdf– NICE?
http://www.mbpct.nhs.uk/medman/prepad/documents/PrescriptionPadJuly2006.pdf
Lancet 1993
Lancet 1993
Prority Medicine (for Europe) WHO 2004 http://mednet3.who.int/prioritymeds/