1 Pharmacometrics Impact on FDA Pharmacometrics Impact on FDA Decisions & Recommendations: Decisions & Recommendations: Past, Present & Future Past, Present & Future Bob Powell, PharmD Director (2/05-1/07), Pharmacometrics, OCP Office of Translational Sciences Joga Gobburu, PhD Acting Director, Pharmacometrics Office of Clinical Pharmacology CDER FDA [email protected]
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1 Pharmacometrics Impact on FDA Decisions & Recommendations: Past, Present & Future Bob Powell, PharmD Director (2/05-1/07), Pharmacometrics, OCP Office.
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Pharmacometrics Impact on FDA Pharmacometrics Impact on FDA Decisions & Recommendations: Decisions & Recommendations:
Past, Present & FuturePast, Present & Future
Bob Powell, PharmDDirector (2/05-1/07), Pharmacometrics, OCP
• Definition: quantitative pharmaco-statistical analysis to answer clinical drug development & regulatory questions & influence decisions
• People who do this work usually have background in clinical pharmacology, biostatistics and have good judgment in therapeutics, drug development and regulatory decisions
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The PastThe Past
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HistoryHistory
Date Center for Drug Evaluation &
Research Director
Office of Translational
Sciences Director
Date Biopharmaceutics to
Clinical Pharmacology
Director
1987- 1993 Carl Peck 1991-1995 Tom Ludden
1994-2005 Janet Woodcock 1995- Larry Lesko
2005- Steven Galson
2006 Shirley Murphy
Clinical Pharmacology Focal Point
Dosage Form Drug Interactions
Dosage Regimen
• Efficacy/Safety
• Personalized medicine
70’s 80’s 90’s 00’s
Lewis Sheiner
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HistoryHistoryTopics/contributions
• Peck-Ludden 87-95– Drug concentration development paradigm
• Individual PK forecasting & individualized Rx• Population PK/PD applications• Pharmacometrics derived evidence of
• Implement EOP2a meetings• Disease model & trial design started (Parkinson’s disease)• QT trial design & concentration-response analysis
– 2005 • Office strategic plan emphasizing PM• Centralized PM• Data warehouse-Software environment
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Opportunities for integration of pharmacokinetics, Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug developmentpharmacodynamics, and toxicokinetics in rational drug development
Peck CC, Barr WH, Benet LZ, et al
Clin Pharmacol Ther 51: 465, 1992
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15 year Impact15 year Impact1992 1992 → 2007→ 2007
• PM roadmap in drug development & regulatory decisions
• Led to FDA guidances (e.g., exposure response, population PK, EOP2a)
• Indexed toxicology to likely human exposure (first in humans guidance)
• Enabled routine prediction of human PK/PD from preclinical data
• Changed information available in NDA package…[drug] preclinical → NDA
• Enabled FDA PM to do current work
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How should we improve it in 2007?How should we improve it in 2007?
• Balance interest in disease, drug & safety
• Account for key decision points, questions & information required
• Decision making mechanism supported by quantitative analysis
• When & how sponsors & FDA communicate
• Extend paradigm through product life-cycle
• Enhanced collaboration between clinical, biostatistics, PM
• Translate accumulated knowledge to better support clinician recommendations & patient decisions
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On their ShouldersOn their Shoulders
• Academics– Lewis Sheiner– Stuart Beal– Sid Riegelman– Leslie Benet– Malcolm Rowland– Tom Tozer– John Wagner– Gerhard Levy– Bill Jusko– Nick Holford– Matts Karlsson – Don Stanski – Don Rubin
• FDA– Roger Williams– Bill Gillespie– Raymond Miller– Bill Bachman– Ene Ette– Jerry Collins– Hank Malinowski– He Sun– Lilly Sanathanan – Stella Machado
• Industry– Rick Lalonde – Sandy Allerheiligan– Mike Hale – Karl Peace – Karl Metzler– Dan Weiner
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The PresentThe Present
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My Fear-based Mental ModelMy Fear-based Mental Model
↑ Failure
↓ Company Value
Merger
Lose Job
Company
Unsafe or ineffective drugs approved
People hurt
Lose confidence in FDA
FDA
Poor Decisions
Insufficient Knowledge
&Decision Process
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My Hope-based Mental ModelMy Hope-based Mental Model
Safe or Effective drugs approved
↑ Health for All
Gain confidence in FDA
FDA
Wise Decisions
Sufficient Knowledge
&Decision Process
Leverage Leverage PointPoint
↑ Success
↑ Health
↑ Company Value
Company
Promotion
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Drug Development DecisionsDrug Development Decisions
• Too Biased– Marketing trumps science– ‘Champions’ trumps team recommendations
• We can make better decisions regarding• Trial design• Dose response• Safety signal• Market Value• Label set for populations, not individual patients…
personalized medicine?
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SIMULATE DOSING REGIMEN
• DOSE
• FREQUENCY
• DISEASE SEVERITY
• DRUG INTERACTIONS
• PEDIATRICS
IMPACT OPPORTUNITIES- MODEL & SIMULATE KEY DECISIONS
• Early decisions more important• Biomarker qualification• ↑ Cross company consortia
FDA refined roles–Decision-making–Consultation–Knowledge-sharing
Changes in FDA– Organization & culture– Funding
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Similar information can be used to answer Similar information can be used to answer questions from different perspectivesquestions from different perspectives
Mission: Create & Share• Train Ph.D’s & fellows in Pharmacometrics• Disease models: Mechanistic & empirical reflecting morbidity & mortality• Clinical trial information to plan a successful trial (placebo, drop-outs, baseline)• Drug models for efficacy & safety• Benefit/Risk research• 5-10 Programs needed
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5 year Direction5 year Direction(Peck, Ludden, Lesko, Murphy, Gobburu, Powell)
• FDA quantitative decision → Mainstream– NDA review decisions
• Drug approval• Label-dosing regimen, 1° and special populations
– QT trial design & analysis– Pediatric written requests– End of Phase 2a meetings– Disease model construction
• Trial design• Biomarker qualification
• FDA EOP2a Meetings: Key to R&D productivity• Model based drug development R&D framework across companies• FDA IT Tools: Rapid access, analysis, report of drug & diseases data• Label: Efficacy/safety → Benefit/risk & graphics• Closer collaboration- medical officer, biostatistics, clinical pharmacology, PM
• Share disease, drug & clinical trial models• Training
– PhD Programs-5 producing 25/year– FDA PM Fellowships: 5 new 2 year fellows/year
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AcknowledgementsAcknowledgements
• Carl Peck• Tom Ludden• Office of Clinical Pharmacology
– Larry Lesko– Reviewing Divisions
• Mehul Mehta• Chandra Sahajwalla• Patrick Marroum• Ramana Uppoor• Brian Booth• Young Moon Choi• Seong Jang• Rashni Ramchandani