how are drugs and vaccines discovered and developed? dr. jeffrey l. sturchio president & ceo,...
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How are drugs and vaccines discovered How are drugs and vaccines discovered and developed?and developed?
Dr. Jeffrey L. Sturchio
President & CEO, Global Health Council
Journalist-to-Journalist Program
National Press Foundation
Cape 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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The path from compound to drugThe path from compound to drug
• Understanding of the biochemical and cellular mechanism
• Whole animal assays
• Metabolism & bioavailability
• Pharmaceutical R&D – stability; formulation strategy;
physicochemical properties
• Preliminary safety data
– initial genotoxicity; short term probe safety studies
• Ancillary pharmacology
• Chemistry– why this compound & how
was it found
• Process chemistry– scale up feasibility; cost
projections
• Clinical & regulatory plans – biochemical measure of
efficacy – 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 development Scientific 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
Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006.
Drug discovery and development is difficult and Drug discovery and development is difficult and requires significant infrastructure and resourcesrequires significant infrastructure and resources Drug discovery and development is difficult and Drug discovery and development is difficult and requires significant infrastructure and resourcesrequires significant infrastructure and resources
Developing a new medicine takes an average of 10–15 years; the Congressional Budget 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 – 2 YEARS6 – 7 YEARS3 – 6 YEARS
NUMBER OF VOLUNTEERS
PHASE 1
PHASE 2
PHASE 3
5250~ 5,000 – 10,000
COMPOUNDS
PR
E-D
ISC
OV
ER
Y
20–100 100–500 1,000–5,000
IND
SU
BM
ITT
ED
ND
A S
UB
MIT
TE
D
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 patients initially and/or recruit more patients during the trial.
Increasing Complexity of Clinical TrialsIncreasing Complexity of Clinical Trials
During the last decade clinical trial designs and procedures have become much more complex, demanding more staff 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 Enrollment Rate
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 18 19 20
Pre
sent
Val
ue (
1990
$M
M)
Average R&D Investment ($202 MM) Cumulative Returns Cover
R&D investment in Year 16
Introduction
Source: Grabowski and Vernon. “Effective Patent Life in Pharmaceuticals.” Forthcoming in The Journalof International Technology Assessment, 1999.
Costs are recovered over a long period…
$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 1990–94. The same analysis found that the total cost 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 reach approval.
Lifetime Sales Compared to Average R&D Costs
New Rx Drugs Introduced Between 1990 and 1994, Grouped by Tenths, by Lifetime Sales
Aft
er-
Ta
x P
res
en
t V
alu
e o
f S
ale
s
(Mil
lio
ns
of
20
00
Do
lla
rs)
…and most marketed drugs don’t recover their costs…and most marketed drugs don’t recover their 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 Biotech Different?,” 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
0
5
10
15
20
25
30
35
Approvals
R&D Spending
No.
of
NM
Es
Ap
pro
ved
$
Billio
ns R
&D
Sp
en
d
*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 drug discovery?
• 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 escalating costs of R&D to the current estimate of ~ US$1 BB
to bring a drug to market
Roadmap for Developing an AIDS Vaccine
Solving theNeutralizingAntibody Problem
Solving theProblem of
How to ControlHIV Infection
Emerging challenges and Emerging 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 developing world?
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Sources: 1Burrill & Company, analysis for PhRMA, 2005–2009 (Includes PhRMA research associates and nonmembers) in PhRMA, “Profile 2008, Pharmaceutical Industry;” PhRMA, “PhRMA Annual Membership Survey,” 1996-2009; 2Adapted from E. Zerhouni, Presentation at Transforming Health: Fulfilling the Promise of Research, 2007; 3NIH Office of the Budget, “FY 2009 President’s Budget Request Tabular Data”, http://officeofbudget.od.nih.gov/ui/2008/tabular%20data.pdf
Federal and Industry Roles in Research and DevelopmentFederal and Industry Roles in Research 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
Translational Research
Clinical Research
Basic Research
Translational Research
NIH3 – $29.4B total – $20.1B research
Government and biopharmaceutical industry research are complementary
““
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Speed, focus and collaboration will drive Speed, focus and collaboration will drive future successfuture success
• Knowledge explosion is still driving demand for new technology investments 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 of early research occurs outside of large pharmaceutical companies
– Tools of drug discovery have been “democratized”; Biotechs are getting much better at producing “drug-like” molecules
– However, development occurs in the major pharma companies – which is where the real costs lie
For further information For 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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Drug discovery and development is difficult and Drug discovery and development is difficult and requires significant infrastructure and resourcesrequires significant infrastructure and resources
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15 IntroductionRegistration
Development
BasicResearch
1
2
2-5
5
5,000 Substances
????? Substances
Product Surveillance
Clinical Tests(Human)
Preclinical Tests(Animal)
Synthesis Examination & Screening
Phase IV
Phase III
Phase II
Phase I
Source: PhRMA
Ye
ars