Is FDA failing us
Or are we failing FDA?
Jonathan C. Javitt, M.D.,M.P.H
Senior Fellow, Potomac Institute for Policy Studies
Former Chair, Health Subcommittee, President’s
Information Technology Advisory Committee,
Don’t take my word for it
•Our [FDA’s] approach to risk
management includes finding ways to
help make sure that drugs we review
are used safely once they’re approved.
•Too often, the drugs, devices, and
other products we regulate are
involved in preventable adverse events.
•As many as 20% of Americans have
experienced some kind of medical
error.
•Preventable errors and complications
involving prescription drugs alone are
responsible for thousands of deaths,
millions of hospitalizations, and
billions of dollars in additional health
care costs each year, not to mention the
unnecessary suffering.
Mark McClellan, M.D., Ph.D.
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
A seemingly vicious circle

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Too few NME’s will be approved this year
The cost of bringing new drugs to market is far
too high and takes too long
Congress and the public have labeled FDA’s drug
safety process as fundamentally flawed
The more pressure that is brought to bear on FDA
to improve drug safety, the more risk averse the
agency becomes
Nobody ever got fired from FDA for witholding
approval on safety grounds
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
The other side of the coin


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The real threat to American lives is not dangerous
drugs, but rather errors in the use of generally
safe and effective drugs
More Americans are harmed by their failure to
receive a needed drug than will ever be harmed
by administration of a harmful drug
The problem lies in the disconnect between
postmarketing surveillance, pharmaceutical risk
management, and clinical practice
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
Today’s question

What is the best way to ensure public safety once
drugs are introduced to the marketplace?
 Yesterday’s
answer  anecdotal reporting
 Today’s answer  database analysis
 Tomorrow’s answer  sentinel systems
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
A Unified Sentinel System: transforming a
vicious circle into a virtuous one
A Sentinel System
Continuously monitors
all available sources of
medical information in
order to identify:
1. Common medical
errors
2. Drug adverse events
and interactions
3. Failure to comply
with care
4. Threatening clinical
parameters
5. Opportunities to
improve care
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
GAO Recognizes the problem
However the proffered solution
will add enormous cost to the
regulatory process and provide
far less benefit than might
otherwise be achieved
GAO does realize, however, that
anecdotal reporting databases for
drug complications are
inherently flawed and that
population surveillance is needed
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
Drug Safety
Health Plan Records Seen as Cost-EffectiveW ay to Identify Risks of Drugs on Market
Analyzing large health plan databases to
detect drug side effects would be a more costeffective way to monitor drug safety than the
risk-minimization plans proposed in a Senate
bill (S. 484), a former head of the Food and
Drug Administration said recently.
Mark McClellan, the former commissioner of
FDA, said that he supports S. 484, the drugsafety legislation sponsored by the chairman
and ranking member of the Senate Health,
Education, Labor, and Pensions Committee,
calling it "the right foundation to build on."
However, he and others who spoke March 21
at a Capitol Hill briefing cast doubt on whether
the legislation makes use of the best type of
postmarket drug-safety surveillance
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
As Safety concerns mount, sponsors have
three basic alternatives
– 100,000 person
safety trials prior to market
approval Cost prohibitive
Construction of ad-hoc
registry programs for each
newly launched drug
10,000
Extremely expensive
Deploy
Sentinel
Database systems in order
to monitor drug safety and
utilization $.50 pmpm
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
The drug safety paradigm must change
While reporting databases can, and should be used
to report rare, life-threatening events, moving to
active surveillance systems enables us to:



Actively keep drugs safe in the marketplace
Improve patient safety by identifying those who
would benefit from therapies they are not
receiving
Potentially launch new drugs much more quickly
into a monitored environment
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
The Same Framework that
addresses the most critical
problems confronting
patient care, also
addresses the challenges
facing postmarket
surveillance and drug
approval
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
The Active Health Care Engine®
Hospital
Claims
Lab
Results
Pharmacy
Claims
Provider
Claims
RN Notes
Clinical
Rules
C
MD / RN
Review
Clinical Review
System
Automated
4. Apply Medical
Intelligence
5. Create
Recommendations
Communication Portal
16 million
covered
lives
Letters
7. Action by Doctor
and Patient
6. Communicate
Recommendations
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting.
November 28, 2006
Can deployed Sentinel Systems save lives
and save cost?
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100,000 member midwestern managed care plan
Selected all members with at least one physician visit
and one pharmacy claim in preceeding 12 months
20,000 members selected per group
Random allocation to Sentinel system with mailed
clinical prompts or to watchful waiting
Study period of 12 months
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Implementation of Recommendations
Adoption
86%
73%
63%
58%
56%
50%
46%
44%
42%
38%
37%
Care Consideration Description
Improve a subtherapeutic INR
Normalize high INR
Monitor for toxicity in amiodarone use
Stop NSAID in anticoagulation
Stop either Viagra or nitrates
Monitor INR with interacting drugs
Monitor INR in Coumadin use
Stop Wellbutrin in patients with seizures
Monitor LFTs in patients on glitazones
Monitor for toxicity in methotrexate use
Stop metformin in patient with renal insufficiency.
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Randomized Prospective Study:
Approximately 1,000 interventions issued in the intervention
group and a similar number observed in the control group
Control
Total Admissions
Study
Difference
1052
936
11%*
Admits/1000
47.55
42.1
11%*
Hospital Bed-Days total
4089
3483
15%*
ALOS
3.89 days
3.72 days
4.5%*
Days per 1000
184.8
156.9
15%**
Total paid
$31.3 MM
$29.6 MM
5.5%**
Inpatient paid
$4.6 MM
$4.1 MM
11%**
Overall cost saving of 6% - 8%
*
**
p<.03
p<.005
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Sentinel Systems in
Postmarketing Surveillance

Reinventing the concept of drug safety
– Keeping drugs safe in the marketplace through early detection
of adverse events
• Enables early intervention
• Enables early implementation of monitoring
• Enables early labeling changes
– Keeping drugs safe in the marketplace by avoiding interactions
and proactive notifying caregivers
– Keeping drugs safe by ensuring clinical monitoring
– Keeping patients safe by increasing compliance with therapy
– Keeping patients safe by identifying those in need of
unprescribed therapy
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Sentinel Systems will actually Increase
appropriate sales of lifesaving drugs

Half of those who would benefit from beta
blockers post MI are not receiving them

Half of those who qualify for ACE inhibitors under
the HOPE trial criteria do not receive them

And so on…
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
Keeping Drugs Safe in the Marketplace

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When Rezulin was approved for the treatment of
diabetes, the possibility of liver failure was well
recognized and all involved were confident that with
proper laboratory monitoring patient safety could be
assured
When the first (predictable) cases of liver failure were
reported, FDA determined that only 9% of physicians
were following the rezulin label and obtaining LFT’s.
Therefore the drug was withdrawn on the grounds
that safety could not be maintained in the
marketplace
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Frequency of pharmaceutical risk management
recommendations:
Clinical Issue
Patients
(N)
Triggering
(%)
Need for LFT’s on Rezulin
155
13%
Need renal monitoring on Metformin
329
19%
Need for INR’s on Coumadin
153
7%
Need for LFT’s on Statins
931
10%
In other words, 87% of physicians in this sample were
monitoring their Rezulin patients (not 9% as FDA thought) and
those who were not monitoring frequently complied with a single
reminder letter.
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Proven Results

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Sentinel systems are currently workable and
deployable
Sentinel systems can play a direct role in
pharmaceutical risk management
Sentinel systems suggest action that Physicians will
accept and implement
The costs of sentinel systems are more than offset
by savings in health care
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Are Sentinel Systems merely a Dream?

25 Million Americans already say NO!
– However, these systems were engineered only for the
purpose of patient safety and care improvement

The next phase is the RHIO –
Regional Health Information Exchange
– First Gateways: 20 million lives this year
– Indiana: 5+ million lives
– New England: 5+ million lives
– RHIOs are being engineered primarily for transportability of
health information, driven by health systems economy, with
patient safety as a secondary opportunity and postmarket
surveillance not even a major topic of conversation.
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
The RHIO environment
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Draws together all known diagnoses, procedures,
admissions, labs, and increasingly other findings
under a common data umbrella.
Privacy and security issues have been legislated
and ironed out.
Provides the ideal environment for post-market
surveillance, in addition to patient safety
The problem is the business model to support
RHIOs – right now they are grant funded
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
Business Case for RHIOS

Today’s case
– 1 in 5 diagnostic tests is performed simply because the
results of previous tests are not available during the time
frame of the medical decision
– 1 in 8 hospital admissions is triggered by events resulting
from failure of information flow in the outpatient environment

Tomorrow’s case
– New drugs will come to the market sooner
– Drugs will be less likely to be withdrawn from the market
because of unexpected and unmanageable toxicities
– Patients will be more likely to be offered critical, lifesaving
drugs
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
The future opportunity


Reallocate current resources spent on episodic
reporting to supporting RHIO initiatives
Create a structure for earlier monitored drug
launches in a RHIO environment with user fees
paid by the sponsors
– Instead of requesting a 10,000 person premarketing safety
study, the safety results from 100,000 patients can be
obtained in a RHIO environment at far lower cost

Replace single product risk management
programs with population based programs that
work through and simultaneously support the
evolving RHIO structure
Jonathan C. Javitt, M.D., M.P.H.: ASENT 2008
Cost Effectiveness
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Sentinel systems cost approximately
$10 per person / year to implement
Cost represents < 0.5% of overall
health care costs
Direct savings exceed costs at least
10-fold, not including the benefits to
industry and FDA of safer drugs,
maintained in the marketplace
Extrapolation of these implications to
the nation suggest that a very modest level of
IT investment (i.e. not universal EHR’s) could
readily save the country in excess of $70 Billion/yr
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006
Think about the potential for doing better, more real-world clinical
studies at a much more affordable cost. For example, postapproval studies could be much cheaper and easier to do, using
clinical protocols administered over the internet via electronic
records, with patients selected and results recorded directly
from electronic medical records. Low-cost clinical trials to be
performed more quickly and easily in real-world medical
settings. And we can use the signals we obtain from our better
surveillance system to work with health care providers, funding
agencies, and health care payers to target these studies more
effectively.
Mark McClellan, MD, PhD
Testimony to the
President’s Information Technology
Advisory Committee -- 2003
Jonathan C. Javitt, M.D., M.P.H.: NEI/FDA Endpoints Meeting. November 28, 2006