How are drugs and vaccines discovered and developed

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How are drugs and vaccines discovered 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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Agenda

• 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 RD?
• Some concluding observations
• QA

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How HIV/AIDS is Treated
Kilby J and Eron J. N Engl J Med
20033482228-2238
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The path from compound to drug

• Understanding of the biochemical and cellular
  mechanism
• Whole animal assays
• Metabolism bioavailability
• Pharmaceutical RD
• 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 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 gt12 years to discover and develop a drug
• Competitive environment
• Level of internal expertise
• Externally collaborate

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Scientific disciplines and development
capabilities 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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Drug discovery and development is difficult and
requires significant infrastructure and resources
Developing a new medicine takes an average of
1015 years the Congressional Budget Office
reports that relatively few drugs survive the
clinical trial process
Sources Drug Discovery and Development
Understanding the RD Process, www.innovation.org
CBO, Research and Development in the
Pharmaceutical Industry, 2006.
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Increasing 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
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.
Source Tufts Center for the Study of Drug
Development, Growing Protocol Design Complexity
Stresses Investigators, Volunteers, Impact
Report, 2008.
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Costs are recovered over a long period
Average RD Investment (202 MM)
Cumulative Returns Cover RD investment in Year 16
Introduction
Source Grabowski and Vernon. Effective Patent
Life in Pharmaceuticals. Forthcoming in The
Journalof International Technology Assessment,
1999.
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and most marketed drugs dont recover their costs
Lifetime Sales Compared to Average RD Costs
After-Tax Present Value of Sales (Millions of
2000 Dollars)
New Rx Drugs Introduced Between 1990 and 1994,
Grouped by Tenths, by Lifetime Sales
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 total cost of developing a new drug was
1.3 billion in 2006. Average RD Costs include
the cost of the approved medicines as well as
those that fail to reach approval.
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 RD Is Biotech
Different?, Managerial and Decision Economics,
2007.
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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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..But as RD spending increases, NME approvals
have not.
No. of NMEs Approved
Billions RD Spend
NME (new molecular entity) total is through
August 22, 2001. RD spend for 2000 and 2001
are estimates. Source Washington Analysis,
LLC and PhRMA
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So why is RD 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?

• 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 RD to the
  current estimate of US1 BB to bring a drug to
  market

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Roadmap for Developing an AIDS Vaccine
Solving the Neutralizing Antibody Problem
Solving the Problem of How to Control HIV
Infection
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Emerging challenges and continuing 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 RD?

• Industry spends more on advertising than on RD?
• 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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Trends in resource allocation to SGA, COGS and
RD in the pharmaceutical industry, 1975-2007
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Federal and Industry Roles in Research and
Development
Government and biopharmaceutical industry
research are complementary
Private Sector 65.2B1

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

NIH3 29.4B total 20.1B research
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 2Adapted from E.
Zerhouni, Presentation at Transforming Health
Fulfilling the Promise of Research, 2007 3NIH
Office of the Budget, FY 2009 Presidents Budget
Request Tabular Data, http//officeofbudget.od.ni
h.gov/ui/2008/tabular20data.pdf
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Speed, focus and collaboration will drive future
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

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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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BACK-UP
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Progression of HIV Infection and AIDS
AIDS
Acute Infection
Symptom-free
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Drug discovery and development is difficult and
requires significant infrastructure and resources
Introduction
15
Product Surveillance
Registration
Phase IV
1
Phase III
2
Clinical Tests (Human)
Phase II
2-5
Development
Years
5
Phase I
Preclinical Tests (Animal)
5,000 Substances
Synthesis Examination Screening
Basic Research
????? Substances
0
Source PhRMA