0. 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,

1. 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.

2. A seemingly vicious circle
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

3. The other side of the coin
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

4. Yesterday’s answer  anecdotal reporting
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

5. 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:
Common medical errors
Drug adverse events and interactions
Failure to comply with care
Threatening clinical parameters
Opportunities to improve care

6. 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

7. 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 cost-effective 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 drug-safety 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

8. As Safety concerns mount, sponsors have three basic alternatives
10,000 – 100,000 person safety trials prior to market approval Cost prohibitive
Construction of ad-hoc registry programs for each newly launched drug Extremely expensive
Deploy Sentinel Database systems in order to monitor drug safety and utilization $.50 pmpm

9. 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

10. The Same Framework that addresses the most critical problems confronting patient care, also addresses the challenges facing postmarket surveillance and drug approval

11. The Active Health Care Engine®
Hospital Claims
Lab Results
PharmacyClaims
Provider Claims
RN Notes
16 million
covered lives
Letters
MD / RN Review C
Clinical Rules
Communication Portal
Clinical Review System
7. Action by Doctor and Patient
Automated
4. Apply Medical Intelligence
5. Create Recommendations
6. Communicate Recommendations

12. Can deployed Sentinel Systems save lives and save cost?
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

13. Implementation of Recommendations

14. Randomized Prospective Study:
Approximately 1,000 interventions issued in the intervention group and a similar number observed in the control group
Control
Study
Difference
Total Admissions
1052
936
11%*
Admits/1000
47.55
42.1
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

15. 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

16. 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…

17. Keeping Drugs Safe in the Marketplace
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

18. 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.

19. Proven Results 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

20. 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.

21. The RHIO environment
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

22. 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

23. 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

24. Cost Effectiveness
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

25. Mark McClellan, MD, PhD Testimony to the
Think about the potential for doing better, more real-world clinical studies at a much more affordable cost. For example, post-approval 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