How Do We Get the Drugs We Need Time for Radical Reform Incentivizing Drug Discovery and Drug Safety

1
How Do We Get the Drugs We Need?Time for Radical
ReformIncentivizing Drug Discoveryand Drug
Safety

• Alastair J.J. Wood MD

2
Drug DevelopmentFDA Issues

• Morale
• Budget
• Transparencyaccess to FDA data
• Safety issuessolutions!
• Supply chain integrity
• New paths to approval
• Incentivizing truly innovative drug development

3
Drug DevelopmentBusiness Issues

• Requires access to considerable capital
• Ties up that capital for prolonged period
• Is high risk
• Risk reduction by replication vs. innovation
• Behavior is driven by incentives
• Has produced transformational health benefits
  recently

4
Mortality Trends in the U.S. Population
Wood AJJ NEJM 2006355618-623
5
Drug DevelopmentSo Whats The Problem?

• Productivity is falling
• Costs are increasing
• Lack cures for most-pressing diseases
• Need new path to approval
• Lack of long term safety data

6
Success Rate Falling In All Phases
Wood AJJ NEJM 2006355618-623
7
Fall in NMEs Submitted to FDA
Frantz, Nature Reviews Drug Discovery 3379, 2004
8
Drug DevelopmentSo Whats The Problem?Costs are
Increasing

• Costs gt840 MillionUnsustainable
• Results in risk averse developmentreformulations/
  combinations replicative
• 30 beta blockers
• 50 NSAIDs
• 34 ACE inhibitors
• 14 Angiotensin Receptor blockers
• New Purple Pill
• Isomer of old purple pill

9
But Not The Drugs We Need
Science 309734, 2005
10
High Risk Drug DevelopmentWhats The Problem?

• Drugs to
• Prevent Alzheimers 0
• Prevent osteoarthritis0
• Can these drugs be developed today?
• Science riskalways present
• But no validated path to approval to follow
• Trial duration might exceed patent duration!
• With no guarantee of success
• End point problems
• ?Hip replacement or ?cartilage narrowing?
• AD prevention or ? amyloid?
• Surrogate end points

11
My Proposal for Radical Change Use exclusivity
as an incentive for

• Demonstration of long term safety
• Head to head comparison studies
• Completion of phase-4 commitments
• Validation of surrogate/biomarkers
• Encourage high commercial risk drug development
• Wood AJJ NEJM 2006355618-623

12
Exclusivity in United States

• Patent protection
• Uruguay roundinternational agreements
• Extended exclusivityHatch Waxman
• Granted by legislation
• Can be altered by legislation

13
No Long Term Safety DataNo Head to Head
Comparisons

• Extended period of exclusivity granted when long
  term safety demonstrated
• Would avoid conditional approval
• Would require FDA approval of study design
• Would usually require comparative studies
• Would provide Head to Head studies
• Wood AJJ NEJM 2006355618-623

14
Conversion of Surrogate/Biomarkersto Clinically
Meaningful end points

• Approval based on surrogate requires
• Conversion to meaningful end point for extended
  exclusivity
• Extended exclusivity ONLY granted when clinical
  end point reached
• Some biomarkers will not correlate
• Resulting in loss of extended exclusivity
• Wood AJJ NEJM 2006355618-623

15
Perverse Current Incentives

• Encourages low risk drug development
• Encourages replicative strategies
• No encouragement of high commercial risk
• No encouragement of paradigm shifting
• For preventive drug study length may exceed
  exclusivity duration!

16
Perverse Current Incentives

• Incentivizes low risk/low benefit research
• Develop an isomer of an approved drugvery low
  risk
• But will receive the same extended exclusivity as
  would a preventive therapy for Alzheimers/Osteoar
  thritis
• Where would you put your money?
• Where should we want the money put?

17
New IncentiveAdditional period of exclusivity
for High-need High-risk drug development

• Advance designation of specific areas
• Independent body IOM or NAS designates
• Restricted to (say) 5-10 areas
• Use of biomarkers possible for initial
  approvalextension granted only after upgrade
• Goal
• To incentivize high-risk/high-need drug
  development
• Wood AJJ NEJM 2006355618-623

18
Definition of High-Need High-Risk Therapeutic
AreasRewarded with Extended Exclusivity

• Absence of effective/nontoxic therapies
• High scientific/biological uncertainty of
  scientific strategies
• Lack of previous path to approval
• Large potential effect on disease burden and
  public health
• Wood AJJ NEJM 2006355618-623

19
However!

• Extended exclusivity only granted to early drugs
  in class (number?)
• Late drugs get only standard (Uruguay Round)
  patent duration unless superior
• Not extended exclusivity as now
• Not for more new purple pills
• Goal is to make truly innovative/superior drugs
  more valuable
• Wood AJJ NEJM 2006355618-623

20
Drug DevelopmentWhats The Solution?

• Need to move to an incentive based systemextend
  exclusivity to-
• Reward innovationfirst ACEi vs. 34th
• Reward long term safety data
• Reward hard end pointsmortality, MI, dementia
  vs. ? cholesterol ?HbA1C
• Ensure mandated studies are completed
• Reward conversion of surrogate end points to
  clinically meaningful end points
• Shorten development timereduce risk
• Wood AJJ NEJM 2006355618-623

21
Drug Safety

• High profile recent problems
• Problems at different levels
• Inability to identify safety issuescounting
• Once identified what do we do?
• Change label
• Withdraw drug
• Does changing a drug label make a drug
  safe/safer?
• Is there even a reasonable hypothesis?

22
Drug SafetyWhats the Problem?

• Indications have changed but we didnt notice
• Treatment of pneumonia
• Short term
• Direct patient benefit
• You know the potential benefit to that patient
• Can assess individual risk benefit
• Know patient who benefits

23
Drug SafetyWhats the Problem?

• Indications have changed but we didnt notice
• Diabetes
• Banting and Best reduction in glucose
• Life savingtransformative
• Today incremental reduction in HbA1C
• May be beneficial if population data are
  replicated by drug
• We are really trying to reduce diabetic
  complicationsnot blood glucose

24
Drug SafetyWhats the Problem?

• Indications have changed but we didnt notice
• Diabetes critical questions
• Does drug reduce diabetic complications?
• Does it increase other risks?
• Is there a net benefit?
• Single measure/surrogate no longer adequate
• Need to demonstrate overall benefit

25
Drug SafetyWhats the Problem?

• Torcetrapib
• Rosiglitazone (Avandia)
• We are not Banting and Best anymore!
• The standard for approval will always be an
  evolving standard
• Fortunately!

26
Some Unpalatable TruthsAbout Drug Safety

• Simply counting bodies does not improve safety
• Excellent Airline Safety not because we know
  exactly how many died last year
• Airline safety reflects systems changes
• We need systems changes to improve drug safety
• Not just improved methods for counting bodies

27
Some Unpalatable TruthsDrug Labeling

• Does anyone think that putting a label on an
  airline ticket (that no one seesdrug label)
  would make it safer to fly?
• Why is drug labeling different?
• Label changes are what we do to improve drug
  safety
• Rational?

28
Drug Labeling
29
Labeling
Show me a patient whose life was saved by a
change in a drug label! Troglitozone many AEs in
spite of label changelabel not followed Many
other examples
30
Drug SafetyWhat is the Solution?

• Demonstration of long term efficacy (hard end
  point) and safety required for extended
  exclusivity
• Approval could be on surrogate BUT
• But exclusivity lost if no demonstration
• Long term (hard end point) efficacy
• Long term overall safety
• Does not hold up approval but incentivizes
  generation of data

31
Will Incentives Work?

• Look at what happened with Pediatric Rule
• 6 month extension provided lots of studies
• But not necessarily useful data!

32
Conclusion

• True innovation should be rewarded
• Drugs that cure/prevent currently incurable
  diseases are more valuable to patients
• Should be more commercially valuable
• Mixing two previously approved drugs gets the
  same exclusivity reward as preventing
  Alzheimerscrazy?

33
Final Word

• We all want safe effective drugs to prevent/treat
  the major diseases of today and tomorrow.
• We all need to be prepared to consider radical
  solutions to achieve that goal.

34

• It is always more comfortable to maintain the
  status quo but the current system is not
  delivering the drugs we need.