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How are drugs and vaccines discoveredHow are drugs and vaccines discovered
and developed?and developed?
Dr. Jeffrey L. Sturchio
President & CEO, Global Health Council
Journalist-to-Journalist Program
National Press FoundationCape Town, South Africa
July 18, 2009
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AgendaAgenda
22 years of innovation in HIV/AIDS treatment
Pharmaceutical innovation today
How does modern drug discovery work?
The clinical trials process
Increasing costs and declining productivity of pharmaceutical research?
A word on HIV vaccine research
Emerging challenges and continuing issues
Facts and myths about drug R&D?
Some concluding observations
Q&A
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How HIV/AIDS is Treated
Kilby J and Eron J. N Engl J Med 2003;348:2228-2238
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The path from compound to drugThe path from compound to drug
Understanding of the biochemicaland cellular mechanism
Whole animal assays
Metabolism & bioavailability
Pharmaceutical R&D
stability; formulation strategy;physicochemical properties
Preliminary safety data
initial genotoxicity; short term probesafety studies
Ancillary pharmacology
Chemistry why this compound & how
was it found
Process chemistry
scale up feasibility; costprojections
Clinical & regulatory plans
biochemical measure ofefficacy
dose projection assure patient safety
Patent
Marketing opinion
Competition
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Scientific approachScientific approach
Is there a rational scientific approach? A genetic or biochemical insight
A specific target or pathway
An available proof of concept
Chemically feasibility Some targets are difficult to approach with small molecules
Long-term perspective
Takes >12 years to discover and develop a drug Competitive environment
Level of internal expertise Externally collaborate
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Scientific disciplines and developmentScientific disciplines and development
capabilities neededcapabilities needed
Biochemistry
Molecular Biology
Cell Biology
Physiology
In vitro Pharmacology
In vivo Pharmacology
Structural Biology
Computational Chemistry
Medicinal Chemistry
Genomics
Drug Metabolism
Process Chemistry
Chemical Engineering
Pharmaceutical Chemistry
Toxicology
Clinical Pharmacology
Clinical Development Statistics
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Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research andDevelopment in the Pharmaceutical Industry, 2006.
Drug discovery and development is difficult andDrug discovery and development is difficult and
requires significant infrastructure and resourcesrequires significant infrastructure and resourcesDrug discovery and development is difficult andDrug discovery and development is difficult and
requires significant infrastructure and resourcesrequires significant infrastructure and resources
Developing a new medicine takes an average of 1015 years; the CongressionalBudget Office reports that relatively few drugs survive the clinical trial process
INDEFINITE
Drug Discovery Preclinical Clinical Trials FDA Review Scale-Up to Mfg.Post-MarketingSurveillance
ONE FDA-APPROVED
DRUG
0.5 2YEARS
6 7 YEARS3 6 YEARS
NUMBER OF VOLUNTEERS
PHASE1
PHASE2
PHASE3
5250~ 5,000 10,000
COMPOUNDS
PRE
-DIS
COVERY
20100 100500 1,0005,000
IND
SUBMITTED
NDASUBMIT
TED
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Definitions:
Procedures: include lab & blood work, routine exams, x-rays & imaging, questionnaire & subjective assessments, invasive procedures, heart assessment,etc.
Protocol: the clinical-trial design plan
Enrollment rate: the percentage of volunteers meeting the increasing number of protocol eligibility criteria (percentage screened who were then enrolled)
Retention rates: the percentage of volunteers enrolled who then completed the study; declining retention rates mean that firms must enroll more patientsinitially and/or recruit more patients during the trial.
Increasing Complexity of Clinical TrialsIncreasing Complexity of Clinical Trials
During the last decade clinical trial designs andprocedures have become much more complex, demanding morestaff time and effort, and discouraging patient-enrollment and retention
1999 2005 Percentage change
Unique Procedures per Trial Protocol(Median)
24 35 46%
Total Procedures per Trial Protocol(Median)
96 158 65%
Clinical-Trial Staff Work Burden(Measured in Work-effort Units)
21 35 67%
Length of Clinical Trial (Days) 460 780 70%
Clinical-Trial-Participant EnrollmentRate
75% 59% -21%
Clinical-Trial-Participant Retention Rate 69% 48% -30%
Source: Tufts Center for the Study of Drug Development, Growing Protocol Design Complexity Stresses Investigators, Volunteers,Impact Report, 2008.
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Years to Recover R&D Costs
($100)
($50)
$0
$50
$100
$150
$200
$250
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1PresentValue(1990$MM
)Average R&DInvestment($202 MM) Cumulative Returns Cover
R&D investment in Year 16
Introduction
Source: Grabowski and Vernon. Effective Patent Life in Pharmaceuticals. Forthcoming in The Journal
of International Technology Assessment, 1999.
Costs are recovered over a longperiod
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$701
$434
$299
$162$87
$39 $21 $6 ($1)
$1,880
$0
$500
$1,000
$1,500
$2,000
1 2 3 4 5 6 7 8 9 10
After-Tax Average R&D Costs
Note: Drug development costs represent after-tax out-of-pocket costs in 2000 dollars for drugs introduced from 199094. The same analysis found that the totalcost of developing a new drug was $1.3 billion in 2006. Average R&D Costs include the cost of the approved medicines as well as those that fail to reachapproval.
Lifetime Sales Compared to Average R&D Costs
New Rx Drugs Introduced Between 1990 and 1994, Grouped by Tenths, by Lifetime Sales
Af
ter-TaxPresentVa
lue
ofSale
s
(Millionso
f2000Dol l
ars)
and most marketed drugs dont recovertheir costsand most marketed drugs dont recovertheir costs
Sources: J. Vernon et al., Drug Development Costs when Financial Risk is Measured Using the Fama-French Three Factor
Model, Unpublished Working Paper, 2008; J. DiMasi and H. Grabowski, The Cost of Biopharmaceutical R&D: Is BiotechDifferent?, Managerial and Decision Economics, 2007.
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The pace of discovery is fast .The pace of discovery is fast .
Human Genome Project complete
Advances in structural biology
Rapid generation of monoclonal antibodies
RNA profiling
Proteomics
Pharmacogenomics
Engineering sciences, informatics
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0
10
20
30
40
50
60
199
0
199
1
199
2
199
3
199
4
199
5
199
6
199
7
199
8
199
9
200
0
2001
*
Approvals
R&D Spending
No.
ofNM
Es
Ap
p ro
ve
d
$B
illionsR&DSpend
*NME (new molecular entity) total is through August 22, 2001. R&D spend for 2000
and 2001 are estimates. Source: Washington Analysis, LLC and PhRMA
..But as R&D spending increases, NME..But as R&D spending increases, NME
approvals have not.approvals have not.
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So why is R&D productivity down?So why is R&D productivity down?
Tackling diseases with complex etiologies?
Demands for safety and tolerability are much higher?
Proliferation of targets is diluting focus?
Genomics has been slow to influence day-to-day drugdiscovery?
Impact of mergers?
Big Pharma model no longer valid?
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Why do drugs fail?Why do drugs fail?
Toxicity
Long term safety is still totally unpredictable
Bioavailability and half life
Cannot be predicted, only guessed
Metabolism
Drug/drug interactions; parent or metabolite
Man
Understanding of pathophysiology is faulty
Dealing with stochastic failures is one of the primary drivers in escalatingcosts of R&D to the current estimate of ~ US$1 BB to bring a drug to
market
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Roadmap for Developing anAIDS Vaccine
Solving theNeutralizingAntibodyProblem
Solving theProblem of
How to ControlHIV Infection
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Emerging challenges andEmerging challenges and
continuing issuescontinuing issues
Dealing with chronic therapy
Simplification, convenience and adherence
Tolerability and reducing toxicities
Managing resistance Combination treatments
New targets
HIV entry inhibitors
HIV integrase inhibitors Maturation inhibitors
The quest for a safe and effective HIV vaccine
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Facts & myths about drug R&D?Facts & myths about drug R&D?
Industry spends more on advertising than on R&D?
Industry is more interested in me-too drugs than in
innovation?
Drugs are discovered by academe?
Patents are a barrier to access?
Industry does not care about diseases of the developingworld?
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Trends in resource allocation to SG&A, COGSand R&D
in the pharmaceutical industry, 1975-2007
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Sources: 1Burrill & Company, analysis for PhRMA, 20052009 (Includes PhRMA research associates and nonmembers)in PhRMA, Profile 2008, Pharmaceutical Industry; PhRMA, PhRMA Annual Membership Survey, 1996-2009; 2Adaptedfrom E. Zerhouni, Presentation at Transforming Health: Fulfilling the Promise of Research, 2007; 3NIH Office of theBudget, FY 2009 Presidents Budget Request Tabular Data, http://officeofbudget.od.nih.gov/ui/2008/tabular%20data.pdf
Federal and Industry Roles inResearch and DevelopmentFederal and Industry Roles inResearch and Development
There is an ecosystem of
science and biotechnology.
Public organizations,
patient organizations,
universities, Congress,
FDA, all of this is an
ecosystem that is envied in
the rest of the world.
E. Zerhouni,
Director of NIH
Private Sector $65.2B1
Clinical
Research
Basic Research
TranslationalResearch
Clinical Research
Basic
Research
TranslationalResearch
NIH3 $29.4B total $20.1B research
Government and biopharmaceutical industry research are complementary
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Speed, focus and collaboration will driveSpeed, focus and collaboration will drive
future successfuture success
Knowledge explosion is stilldriving demand for new technologyinvestments to support future innovation (genomics, etc.)
Focus must be in making these investments pay
Shift from blockbuster strategies to therapeutic areas of focus
Pharmas addressing unmet medical needs are most likely to survive
Greater pharma reliance on external research and biotech innovation
Vast majority ofearlyresearch occurs outside of large pharmaceuticalcompanies
Tools of drug discovery have been democratized; Biotechs are gettingmuch better at producing drug-like molecules
However, development occurs in the major pharma companies which iswhere the real costs lie
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For further informationFor further information
www.innovation.org
www.keionline.org
www.msfaccess.org
www.dndi.org
www.phrma.org
www.ifpma.org
www.clinicaltrials.gov
www.who.int/intellectualproperty/en
www.who.int/phi/en
www.iavi.org
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http://www.innovation.org/http://www.keionline.org/http://www.msfaccess.org/http://www.dndi.org/http://www.phrma.org/http://www.ifpma.org/http://www.clinicaltrials.gov/http://www.who.int/intellectualproperty/enhttp://www.who.int/phi/enhttp://www.iavi.org/http://www.iavi.org/http://www.who.int/phi/enhttp://www.who.int/intellectualproperty/enhttp://www.clinicaltrials.gov/http://www.ifpma.org/http://www.phrma.org/http://www.dndi.org/http://www.msfaccess.org/http://www.keionline.org/http://www.innovation.org/ -
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BACK-UPBACK-UP
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Progression of HIV Infection andAIDS
AIDSAcute Infection Symptom-free
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Drug discovery and development is difficult andDrug discovery and development is difficult and
requires significant infrastructure and resourcesrequires significant infrastructure and resources
0
15 IntroductionRegistration
Development
BasicResearch
1
2
2-5
5
5,000Substances
?????Substances
ProductSurveillance
Clinical Tests(Human)
Preclinical Tests
(Animal)
SynthesisExamination& Screening
Phase IV
Phase III
Phase II
Phase I
Source: PhRMA
Years