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Comparative effectiveness research in the neurosciences.

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MESSAGE FROM THE EDITOR
Comparative Effectiveness Research in the
Neurosciences
There has been a lot of buzz about comparative effectiveness
research recently. Defined as research that evaluates interventions already in clinical use, comparative effectiveness research has been touted as part of the answer to rising medical
costs1 and is explicitly targeted to receive over $1 billion USD
in recent versions of the economic stimulus package. How it
will affect clinical researchers and ultimately impact the clinical neurosciences remains to be seen.
Advancing science and health are the major goals driving
the biomedical research agenda. As testimony to the success
of this agenda, we have witnessed substantial gains in health
in the US since the birth of the NIH extramural granting 63
years ago, with an increase in life expectancy from 67 in 1946
to 78 years in 2004,2 and with dramatic declines and even
elimination of impactful diseases. Biomedical research is not
responsible for all these gains, but its important role is undeniable.3
The health advances wrought by biomedical research
have come at a cost. Most medical interventions are associated with increased cost to society, with only a handful actually producing cost savings, even when lost productivity is
considered.3 As knowledge has increased thanks to research,
clinical practice has become more evidence based with greater
gains in health; however, the price tag has been largely ignored.
At an average expenditure of $5,267 annually per person
in 2002, healthcare costs are greater in the US than anywhere
else in the world, with Switzerland a distant second at $3,446
per year.4 Greater spending has not translated to better
healthcare overall, with a variety of measures, such as life expectancy and infant mortality, putting the US somewhere in
the middle or even near the bottom compared to other highincome countries. Furthermore, if the rate of inflation in
healthcare spending — recently 2.5% greater than overall annual inflation — continues, federal healthcare spending will
require the entire current US federal budget by the year
2045.4 Clearly, as a society, we need to focus on healthcare
value and not just absolute health improvements.
The disconnection between healthcare costs and gains is
the primary motivator for comparative effectiveness research.
As far back as 2003, there has been a call to directly compare
drugs in actual use, with a failed bill attempting to set up a
modest fund for this purpose.5 Now 6 years later, healthcare
costs have continued to increase with only modest measurable gains in health, and with a new administration and a
focus on value, comparative effectiveness research has become
a central component of healthcare reform.
A6
Αnnals of Neurology
Not everyone is in favor of a government-sponsored initiative for comparative effectiveness research. Some fear that
a national program will usher in a new era of government intrusion into the physician-patient relationship, signal the beginning of healthcare rationing, and disincentivize the
pharmaceutical, biotechnology and medical device industries.
One argument goes as follows: what if a therapy is found to
be only marginally effective at a population level but is more
effective in some situations, for example in certain subgroups
of patients or in some ethnic and racial groups? Medicare
might use incomplete or flawed comparative effectiveness
data to deny coverage of useful therapies, and private insurers would be tempted to follow Medicare’s lead. Although
softening language has been added to the current bill, and its
sponsors have stated that its purpose is not to support decisions about coverage, many Republican legislators and conservative groups remain in opposition.
Although we often think of clinical trials as designed to
introduce new therapies, many could qualify, at least in broad
terms, as comparative effectiveness studies. To determine
NINDS experience in funding trials that compared alternatives already used in clinical practice, we reviewed data from
a prior study of the impact of the NINDS trial portfolio.6 Of
the 31 trials with funding completed before 2000, 17 compared management options that were already being used in
practice at the time, and therefore could qualify as comparative effectiveness research (Table). These trials accounted for
$267 million of the total $335 million budget for the trial
program, after inflation to 2004 dollars using the medical
care component of the Consumer Price Index. Some of the
ongoing large-scale trials in the NINDS portfolio are also
comparative effectiveness studies, including the CREST trial
comparing carotid endarterectomy to stenting, ARUBA comparing intervention to no intervention in patients with arteriovenous malformations, a trial performed in the Clinical
Research Collaboration comparing propranolol and topiramate for migraine prophylaxis, and the CombiRx trial comparing the combination of glatiramer acetate and beta
interferon to each agent alone. Thus, comparative effectiveness research is a major focus of trials funded by NINDS.
The NINDS portfolio of trials comparing interventions
already used clinically diverges from the target of proposed
new programs in several respects. First, these trials all restrict
entry to a small subset of the population treated in practice,
and subjects are often monitored in ways that are inconsistent
with routine care. This changes the focus to efficacy, rather
than effectiveness, and potentially prevents generalizing re-
Vol 65 No 2 February 2009
.
Table. NINDS-Sponsored Trials Comparing Interventions Already in Clinical Practice
Trial Title
Randomized Indomethacin Germinal
Matrix /Intraventricular Hemorrhage
Prevention Trial
Diazepam for Acute Repetitive Seizures
Active
Intervention
Indomethacin
Control
Intervention
Placebo
Target
Population
Very low birth
weight neonates
Superior
Intervention
Active
Cost of
Trial
$8,875,271.77
Diazepam rectal gel
Placebo
Active
$1,563,303.38
Asymptomatic Carotid Artery Stenosis
Collaborative Study
Carotid
endarterectomy
Medical therapy
Active
$43,320,427.97
Stroke Prevention In Atrial Fibrillation
I
North American Symptomatic Carotid
Endarterectomy Trial
Warfarin or aspirin
Placebo
Acute repetitive
seizure
Asymptomatic
internal carotid
artery stenosis
Atrial fibrillation
Active
$16,093,548.04
Carotid
endarterectomy
Medical therapy
Active
$64,033,234.16
Phenytoin
Placebo
Symptomatic
internal carotid
artery stenosis
Post traumatic
seizures
Acute spinal
cord injury
Acute spinal
cord injury
Early Parkinson's
disease
Active
$2,278,077.76
Active
$6,330,642.45
Active
$12,639,012.97
Active
$34,015,598.08
Patients undergoing
carotid
endarterectomy
Atrial fibrillation
Control
$3,920,504.47
Control
$18,695,305.37
Control
$29,198,825.66
No Difference
$5,475,726.35
No Difference
$5,753,116.22
No Difference
$7,941,149.59
No Difference
$3,105,610.96
No Difference
$3,559,806.67
Dilantin for Seizure Prophylaxis after
Brain Trauma
National Acute Spinal Cord Injury
Study II
National Acute Spinal Cord Injury
Study III
Deprenyl/Tocopherol in Parkinson
Disease (DATATOP)
Methylprednisolone
Placebo
Methylprednisolone,
long duration
Tocopherol/
deprenyl
Methylprednisolone,
short duration
Placebo
Aspirin and Carotid Endarterectomy
High-dose aspirin
Low-dose aspirin
Low-dose warfarin +
aspirin
Superficial temporalmiddle cerebral
artery bypass
Valproate
Standard warfarin
High-dose
epinephrine
Warfarin
Low-dose
epinephrine
Aspirin
Ischemic stroke or
transient ischemic
attack
Post traumatic
seizures
Cardiopulmonary
resuscitation
Atrial fibrillation
Methylprednisolone,
high dose
Percutaneous
discectomy
Methylprednisolone,
low dose
Conventional
discectomy
Acute spinal cord
injury
lumbar disc
herniation
Stroke Prevention In Atrial Fibrillation
III
Extracranial/Intracranial Arterial
Anastomosis Study
Valproate for Seizure Prophylaxis after
Brain Trauma
Brain Resuscitation Clinical Trial III
Stroke Prevention In Atrial Fibrillation
II
National Acute Spinal Cord Injury
Study I
Conventional vs. Percutaneous
Discectomy - A Clinical Trial
Summary (total)
Medical therapy
Phenytoin
$266,799,161.85
Trial costs were inflated to 2004 dollars based on the medical care component of the Consumer Price Index.
sults to the full population actually treated in practice. New
methods beyond traditional randomized trials are being developed to better evaluate treatments in routine use while attempting to control the difficult problem of confounding.7
Second, the primary focus of NINDS-sponsored trials remains the advancement of more effective therapies. Rather
than comparing equally accepted alternatives, NINDS trials
often compare one intervention that is used infrequently
(often considered riskier or more invasive) with another that
dominates practice. The agenda for comparative effectiveness research will have different priorities. With cost and
value major foci, we will see more studies attempting to establish that a cheaper intervention is no less effective than a
more expensive one.
As demonstrated by our current and past research agenda,
there are many questions in the clinical neurosciences that
are excellent targets for comparative effectiveness research.
In addition to the topics previously or currently studied, there
are numerous clinical questions that come up daily and could
impact neurological care. For example, when should new
generation anticovulsants be favored over their predecessors?
When is an echocardiogram worth the cost after stroke? Are
newer sleep medications better tolerated than their predecessors and worth the cost? Who really benefits from lumbar
diskectomy? These are the kinds of questions our patients
and trainees ask frequently, and it will be nice to have evidence to answer them rather than relying on messaging from
marketers and on our own personal experience.
Clinical neuroscientists must be ready to offer questions
and research plans in comparative effectiveness or the agenda
may not adequately represent us. As the caretakers of diseases with tremendous impact on individuals and at a popu-
© 2009 American Neurological Association
.
Published by Wiley-Liss, Inc., through Wiley Subscription Services
A7
lation level, we have a responsibility to represent our patients
during the birth of this field, particularly given the substantial investment expected as part of the economic stimulus
package. Perhaps now is the time to begin to come together
with a plan for participation and leadership.
S. Claiborne Johnston, MD, PhD and Stephen L. Hauser, MD
Editors
References
1. Orszag PR. Research on the Comparative Effectiveness of
Medical Treatments: A Congressional Budget Office Paper.
Washington: Congress of the United States, 2007.
2. Arias E. United States life tables, 2004. Natl Vital Stat Rep
A8
Message from the Editor
2007;56:1-39.
3. Murphy KM, Topel RH, eds. Measuring the Gains from Medical Research. Chicago: University of Chicago, 2003.
4. Wilensky GR. Developing a Center for Comparative Effectiveness Information.
Health affairs (Project Hope)
2006;25:w572-585.
5. Lyles A. Comparative Effectiveness Research: NICE for the
NHS, but False Starts for the US. Clinical Therapeutics
2008;30:1702-1703.
6. Johnston SC, Rootenberg JD, Katrak S, et al. Effect of a US
National Institutes of Health Programme of Clinical Trials on
Public Health and Costs. Lancet 2006;367:1319-1327.
7. Lohr KN. Emerging Methods in Comparative Effectiveness
and Safety: Symposium Overview and Summary. Med Care
2007;45:S5-8.
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