National Health Policy Conference February 6, 2006 Applications of Drug Safety Information – One Industry Perspective Tim Franson, MD Vice President Global

National Health Policy Conference

February 6, 2006

Applications of Drug Safety Information – One Industry Perspective

Tim Franson, MDVice President Global Regulatory Affairs

National Health Policy Conference February 6, 2006

Company ConfidentialCopyright © 2000 Eli Lilly and Company

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Applications of Drug Safety Information – One Industry Perspective

• Framing / introduction– “If it wasn’t for time, everything would happen all at once”

Stephen Hawking or Yogi Berra?

– Safety (or, more appropriately benefit-risk) evolves over time

– Beginning with the end in mind: Patients first Fair, balanced comprehensive (re) assessments Benefit-risk perspectives (neither in isolation)

Future progress depends on Collaboration,

Communication, Common standards clarified, and

Commitment – “4-C Progress”



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Applications of Benefit/Risk Information

• Objectives– Definitions and common assumptions– Moving from “As is” to “Should be”

• Where are “we” today?– Provincial approaches (industry, regulations, academia)– Perceptual flaws

• Industry: current “risk management” practices– Pre NDA– At approval– Post approval – Summary industry overview issues



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Applications of Benefit/Risk Information (cont’d.)

• Where “we” must change – and why

• Conclusions and Ways forward– Glasnost and Perestroika ?

– 4-C’ing progress

– Patients and public health first (the key “what“) and balanced benefit-risk assessments (the key “HOW”)



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Definitions and Common Assumptions

The importance of defining words and their context:

• Applications – “layers”• Safety• Risk• Benefit• Benefit-risk• Risk Management



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Safety – a feeling of being secure, certainty

Safety is the condition of being protected against failure, damage, error, accidents, or harm. Protection involves here both causing and exposure. Safety is often in relation to some guarantee of a standard of insurance to the quality and unharmful function of a thing or organization.

From Wikipedia, the free encyclopedia.

Is totally safe feasible?



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Risk – the possibility that something will go wrong

Risk is the potential harm that may arise from some present process or from some future event. In everyday usage, “risk” is often used synonymously with “probability”, but in professional risk assessments, risk combines the probability of a negative event occurring with how harmful that event would be.


Is zero risk a practical goal?



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Benefit – an advantage, help or aid

• Services or value provided by a program.

• Employee benefits: non-monetary employment compensation.

• Benefit, an album by Jethro Tull.




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Risk-Benefit Analysis

Risk-benefit analysis is the comparison of the risk of a situation to its related benefits.

For research that involves more than minimal risk of harm to the subjects, the investigator must assure that the amount of benefit clearly outweighs the amount of risk. Only if there is favorable risk benefit ratio, a study may be considered ethical.

The Declaration of Helsinki states biomedical research cannot be done legitimately unless the importance of the objective is in proportion to the risk to the subject. The Helsinki Declaration [1] and the CONSORT statement [2] stress a favorable risk benefit ratio.




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Risk Management

Generally, Risk Management is the process of measuring, or assessing risk and then developing strategies to manage the risk. In general, the strategies employed include transferring the risk to another party, avoiding the risk, reducing the negative effect of the risk, and accepting some or all of the consequences of a particular risk.




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Emerging Elements and New Requirements of Risk Management Plans

• Label restrictions

• Toxicology studies

• Restricted drug distribution

• Patient registries

• Educational initiatives

• Restrictions to DTC advertising and/or product promotion



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Moving from “As Is” to “Should Be”

Assessing enablers vs. impediments• People “stakeholders”• Processes• Desired outcomes • Conflicts of (dis) interest

Specificity of “fixes” – systemic vs. focused• Approval• Post-approval



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Where are “we” (Healthcare Enterprise) Today? (As-is Issues)• Approaches pre-approval: more coordinated, NOT public health issue per se

• Provincial approaches (post approval)– Industry RMP

Routine safety surveillance – massive Response to regulator queries (disparity of criteria from FDA vs. MHRA

vs. CHMP, etc. for near-identical issues: results appear “gamed”)

– Agency RMP Labeling Drug Watch – (observations without proposed actions) Other enforcement

– Academia “Publish or Perish”



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As-is Issues (cont’d.)

Perceptual flaws – amplifies concerns for “out of control” systems

The Bill Buckner Syndrome– Every safety finding highlighted – in isolation

– Plenty of “blame and shame” to go around – but NOT representative (and often NOT accurate)

Industry – transparency, AD suicidality in children, Vioxx, etc.

Agency – PDUFA tainted, Vioxx, whistleblowers, etc. Academia – cloning fraud, Lancet-NSAID fabrication,

Hopkins hexamethonium death, IRB “closures” etc. Confounders: counterfeit drugs, nutraceuticals, etc.



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All real plus most “spun” – None acceptable

None the mainstream – NOT representative

No audit process across the enterprise• Industry (by regulators – in depth/detail)• Agency (by OIG-periodically)• Academia (highly variable – absent)



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Aggregate impact of provincial approaches and perceptual flaws

• Public confusion and erosion of trust

– Stakeholder “mud-wrestling”

• Exceptions viewed as representative

• Health care enterprise appears alarmingly fragmented and out of control – and in need of policy fixes



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Industry – Current Risk Management Practices

• Pre-NDA– 100% data from sponsor

• At approval– Translating volumes of data onto label

• Post approval – Big “R” – little “b”



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Current Practices – Overview & Issues

pre NDA

NDA review

Label

Post-approval Commitments

Label changes

Drug Watch

Benefit

Periodic

By indication (ISE)

Claims

Some

Rare

Brief

Risk

Ongoing (DMB)

Comprehensive (ISS)

Contr/Warn/Prec/AE

Detailed RMPs

Often/detailed

Detailed

Benefit-Risk

Periodic

ISBR Approval Pkg.

NOT routinely

? implied -

NONE

NONE



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Where “we” Must Change – and WhyPolicy initiatives in circulation

– Independent safety office – contrary to benefit-risk integrative view (as usually occurs in practice environment)

– More intensive risk communication – sustains R > b imbalances

Policy options– Glasnost – Perestroika

What are the policy standards (floor vs. ceiling) and set-points for comparisons (ala currency exchange rates, for B/R)?



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Conclusions and Ways Forward

4-C Progress

Collaboration

Communication

Common standards clarified

Commitment



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• Benefit-risk• Confidence/integrity

Accentuate the positives (collaborate ! )

Eliminate the negatives (clarify standards) and…

Don’t break the rules (compliance ! ) rather revise them: Shaping common standards for patient benefit without impeding innovation/access/care practice (PDUFA-4, Pilots, etc.) via…

Proactive Ways Forward…

Documents

National Health Policy Conference February 6, 2006 Applications of Drug Safety Information – One Industry Perspective Tim Franson, MD Vice President Global