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Advanced Modeling Considerations within a
Comparative Effectiveness Research Framework
Jim Murray, Ph.D.
THE 35th ANNUAL MIDWEST BIOPHARMACEUTICAL STATISTICS
WORKSHOP
BALL STATE UNIVERSITY ALUMNI CENTER, MUNCIE, INDIANA
May 22nd, 2012
WHY CER? Why Now?
US Health Care System
US Healthcare is a fragmented System with significant variability in
Process of Care & Patient Outcomes
Medical Expenditure/Enrollee
• Heterogeneous Delivery Models
• Inadequate Access & Coverage
• Misaligned financial “incentives”
& “disincentives”
• Misplaced Financial Risk
• Perspective Oriented
3
Source: Dartmouth Atlas Project, The Dartmouth Atlas of Health Care.
Relationship Between Quality of Care and Medicare Spending:
As Expressed by Overall Quality Ranking, 2000–2001
Data: Medicare administrative claims data and Medicare Quality Improvement Organization program data. Adapted and
republished with permission of Health Affairs from Baicker and Chandra, “Medicare Spending, The Physician Workforce,
and Beneficiaries’ Quality of Care” (Web Exclusive), 2004.
Source: McCarthy and Leatherman, Performance Snapshots, 2006. www.cmwf.org/snapshots
Unsustainable Growth in Health Care Costs
CBO : Research on the Comparative Effectiveness of Medical Treatments: Issues and Options for an Expanded Federal Role,
December 2007
CER Concept and Definitions
Comparative Effectiveness Research
Other definitions offer considerable overlap
Organization
Definition
American College of Physicians
Evaluation of the relative (clinical) effectiveness, safety and cost of 2 or more medical
services, drugs, devices, therapies, or procedures used to treat the same condition.3
Institute of Medicine (IOM) –
Roundtable on Evidence-Based
Medicine
Comparison of one diagnostic or treatment option to ≥1 others. Primary CER involves the
direct generation of clinical info on the relative merits or outcomes of one intervention in
comparison to ≥1 others. Secondary CER involves the synthesis of primary studies to allow
conclusions to be drawn.4
Agency for Healthcare Research
and Quality (AHRQ)
A type of health care research that compares results of one approach for managing a disease
to results of other approaches. CER usually compares ≥2 types of treatment, such as different
drugs, for the same disease but it can also compare medical procedures and tests. The
results can be summarized in a systematic review.5
Medicare Payment Advisory
Commission (MedPAC)
Evaluation of the relative value of drugs, devices, diagnostic and surgical procedures,
diagnostic tests, and medical services. By value, it is meant the clinical effectiveness of a
service compared with its alternatives.6
Congressional Budget Office (CBO)
A rigorous evaluation of the impact of different options that are available for treating a given
medical condition for a particular set of patients. Such research may compare similar
treatments, such as competing drugs, or it may analyze very different approaches, such as
surgery and drug therapy.7
Center for Medical Technology
Policy (CMTP)
The direct comparison of existing health care interventions to determine which work best for
which patients and which pose the greatest benefits and harms. The core question of
comparative effectiveness research is which treatment works best, for whom, and under
what circumstances.8
Comparative Effectiveness Research
Distinguishing characteristics
1.
Informs a specific clinical decision from the individual patient perspective or a
health policy decision from the population perspective
2.
Compares at least two alternative interventions, each with the potential to be
“best practice”
3.
Describes results at the population and subgroup levels
4.
Measures outcomes—both benefits and harms—that are important to patients
and decision makers
5.
Employs methods and data sources appropriate for the decision of interest
(e.g., observational studies, pragmatic trials, systematic reviews)
6.
Conducted in settings that are similar to those in which the intervention will be
used in practice
Committee on Comparative Effectiveness Research Prioritization – Institute of Medicine. Initial
National Priorities for Comparative Effectiveness Research. The National Academies Press, 2009.
Drug vs. drug
9
Lifestyle vs. drug
Screening vs. usual care
Drug vs. device
What’s it really all about….
CER Statistical and Methodological
Challenges
Current PCORI Request for Information on a
Transformational Framework (Proposed Release May 2012)
Intrinsic translation framework components
• Internal validity (bias)
• External validity (generalizability, or applicability to non-study settings
and populations)
• Precision (Sample size, length of follow-up, etc.)
• Heterogeneity in risk or benefit (e.g. subgroup or “personalized”
evidence)
• Ethical dimensions of the study (including considerations of risk-benefit
balance and study burden for study participants)
Extrinsic translation framework components
• Time urgency (e.g., rapidly changing technology, policy or public health
needs)
• Logistical constraints (e.g., feasibility of collecting information from
participants, number of participants available, study complexity)
• Data availability, quality and completeness
IF CER was Simple…..
“All models are wrong, some are useful” – George Box
• Efficacy vs. effectiveness
• Head to Head vs. Indirect comparisons
• Bias from non-representative populations
• Average treatment effects may obscure heterogeneity
of treatment response in subpopulations
– Heterogeneity in risk or benefit (e.g. subgroup or
“personalized” evidence)
• Signal Detection – what might we find from a CER
analysis
– Types of results
– Precision vs. accuracy/validity (Sample size, length of
follow-up, etc.)
CER plays a key role in generating evidence for
clinical and policy decision-making
CAN IT WORK?
DOES IT WORK?
IS IT WORTH IT?
CER
RCTs
EBM
HTA
(Evidence-Based Medicine)
CLINICAL
GUIDELINES
PATIENT
LEVEL
DECISION
MAKING
Source: Drummond et al, 20089
CONDITIONAL COVERAGE
COVERAGE
DECISION
MAKING
What is clinical research?
• Research that takes place in clinical settings
– Case studies
– Case series
– Descriptive & retrospective studies
– Clinical trials
– Randomized controlled trials
Efficacy vs. Effectiveness
• What is the best evidence?
– minimizes bias to the greatest extent possible,
– pertinent to clinical practice.
• The evidence most highly valued and ultimately judged to be the
best may differ based on which perspective predominates.
– efficacy and effectiveness approaches to research.
– assumed to be synonyms, the are not
– are often used incorrectly
• Which question we answer (efficacy or effectiveness) will dictate
or is dictated by
– Data Source
– Study Design
– Analytical Methods
– Generalizabilty
Efficacy and effectiveness studies optimize different aspects of
validity…
clinical research [intervention] studies continuum:
Internal
Validity
External
Validity
Efficacy
Experimental
(RCTs)
Effectiveness
Quasi-experimental/
Observational designs
Most studies fall somewhere in between these anchors
From: Winstein & Lewthwaite, Eugene Michels Forum: CSM, Nashville TN, February 7, 2004
Comparing Pragmatic vs. RCT and Observational
Characteristic
RCT
Pragmatic
Observational
Focus
Efficacy and safety; assess
mechanistic effect; Can it work
Effectiveness and safety; assess /
inform decision-making; Does it work
under usual care conditions?
Effectiveness and safety; Does it
work in actual practice?
Setting
Ideal / artificial
Real-world routine care (with
potential minor departures)
Real-world routine care
Population
Strictly defined; homogenous
Typically broad; heterogeneous
Broad; heterogeneous
Randomization
Yes
Typically yes
No
Blinding
Typically yes
No
No
Interventions
Fully interventional
Minimally interventional (e.g., rand.)
Non-interventional
Outcomes
Clinical surrogates; short term
Longer term outcomes; PROs
Long term outcomes; PROs
Sample Size
Typically small
Typically larger
Typically large
Validity
High internal ( bias); low
external ( generalizability)
Moderate internal; moderate to high
external
Low internal; high external
Prospective/Retro
Prospective
Prospective
Prospective or retrospective
Comparable cost
Higher
Moderate
Lower
Example sub design
Adaptive design
LST; adaptive design
Database studies, cohort, casecontrol, cross-sectional
Pragmatic trials
•
Pragmatic trials are prospective medical research studies that have minimal
interventional activities*, such as randomization, while maintaining routine care of
the subjects. The goal of pragmatic trials is to provide comparative effectiveness
evidence applicable to a broad range of patients and intended for health care
decision makers to make informed health care decisions.
•
Pragmatic trials take place during phase 3b and phase 4 of study drug
development and can involve drug or non-drug interventions, such as a patient
education program. They can be used in support of registration or for nonregistration purposes, or to evaluate the economic impact of therapy. They tend
to be simpler than RCTs and have less data collection.
•
Practical approaches are used to design and implement pragmatic trials. The level
of pragmatism can be measured on several domains (see next slide) such as:
practitioner expertise, intervention flexibility, eligibility criteria, types of outcomes,
intensity of follow-up, and adherence monitoring.
* minimal interventional activities means limiting the number and degree of
controlled conditions, that is, departures from standard routine care
Head to Head vs. Indirect Comparisons
Head to Head comparison
comes from a trial where
A was directly compared
to B.
Indirect Comparison
comes from multiple
studies where A and B may
have been compared to
the same comparator (i.e.,
C) but have never been
compared to each other in
the same study,
What is indirect comparison? Fujian Song BMed MMed PhD Reader in Research Synthesis, Faculty of Health, University of East Anglia
www.whatisseries.co.uk http://www.medicine.ox.ac.uk/bandolier/painres/download/whatis/What_is_ind_comp.pdf
Indirect Comparisons
•
•
•
•
Indirect comparison refers to a comparison of different healthcare interventions using
data from separate studies, in contrast to a direct comparison within randomized
controlled trials. Indirect comparison is often used because of a lack of, or insufficient,
evidence from head-to-head comparative trials.
Naive indirect comparison is a comparison of the results of individual arms from different
trials as if they were from the same randomized trials. This method provides evidence
equivalent to that of observational studies and should be avoided in the analysis of data
from randomized trials.
Adjusted indirect comparison (including mixed treatment comparison) is an indirect
comparison of different treatments adjusted according to the results of their direct
comparison with a common control, so that the strength of the randomized trials is
preserved. Empirical evidence indicates that results of adjusted indirect comparison are
usually, but not always, consistent with the results of direct comparison.
Basic assumptions underlying indirect comparisons include a homogeneity assumption
for standard meta-analysis, similarity assumption for adjusted indirect comparison and
consistency assumption for the combination of direct and indirect evidence. It is
essential to fully understand and appreciate these basic assumptions in order to use
adjusted indirect and mixed treatment comparisons appropriately.
What is indirect comparison? Fujian Song BMed MMed PhD Reader in Research Synthesis, Faculty of Health, University of East Anglia
www.whatisseries.co.uk http://www.medicine.ox.ac.uk/bandolier/painres/download/whatis/What_is_ind_comp.pdf
Bias and Generalizability
Outcome
True Estimate of Effect
Biased Estimate of
effect
c
Oval contains full target population
Inclusion/Exclusion
Criteria for an RCT
If it were not for the
great variability among
individuals, medicine
might as well be a
science and not an
art.”
“
Sir William Osler, The Principles and Practice
of Medicine 1892
Heterogeneity of Treatment Effects
24
Reprinted from Kravitz et al. Milbank Q. 2004;82:661– 687
Analytical Strategy depends on source of
Population Heterogeneity
•Diversity in intrinsic population characteristics
•Underlying disease variability
•Multiple relevant targets for intervention
Low Hanging
Fruit
•Differential ADME (efficacy and/or toxicity)
•Disease adaptation leading to treatment resistance
Company Confidential
Copyright © 2000 Eli Lilly and Company
25
Signal Detection
What can come from CER
• A > B or B > A
• A ≥ B or B ≥ A
• A=B
• A~B
• A?B
• A? B ? C yet A > C
Superiority (Or inferiority)
Better or Same as
• May be conditional
Identical (rare)
Equivalence (functional)
• Doesn’t guarantee
interchangeability
Unknown due to Availability,
Quantity or Quality of evidence
Semi-order
Semi-Orders – Is there any hope?
• a Semi- order is a type of ordering that may
be determined for a set of items with
numerical scores by declaring two items to be
incomparable when their scores are within
some threshold of each other and otherwise
using the numerical comparison of their
scores.
– Precision
– Sample Size
- Power
- Meaningful Tx Effects
There is No Free Lunch
• Accuracy and certainty can be improved only if
additional information, that is both relevant and
appropriate, is included in the analysis.
• Bayesian methods might bring additional information
by including “prior information”
– Finding, representing and justifying the appropriate and
relevant “Prior” information can be “difficult”.
What to think about it all….
Final Thoughts – evolving and to be continued…
• The US Health Care system must develop high-quality,
timely, and relevant CER to help inform individual
treatment decisions made by physicians and patients.
• CER must not be used as a blunt policy instrument for
cost control.
• All scientifically valid data from broad ranges of data
sources (i.e., EMRs, retrospective data, etc.) and study
designs (e.g., RCTs, Observational Studies and
Pragmatic Clinical Trials) for the clinical question under
consideration should be included given appropriate
accommodations for known limitations.
Improved Quality of Care and Patient Outcomes
Good News….
Our future’s so
bright we gotta
wear shades
What do we do about it?
There are many
statistical issues that
need to be addressed
made able to conduct
CER in a valid manner.
Several sessions over
the next two days will
discuss and address
them
Sidney Harris, Used with Permission
Discussion