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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 . Agenda. 22 years of innovation in HIV/AIDS treatment

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How are drugs and vaccines discovered and developed
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


Agenda
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 R&D?

  • Some concluding observations

  • Q&A


How are drugs and vaccines discovered and developed

How HIV/AIDS is Treated

Kilby J and Eron J. N Engl J Med 2003;348:2228-2238


The path from compound to drug
The path from compound to drug

  • 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

  • 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


Scientific approach
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 >12 years to discover and develop a drug

  • Competitive environment

  • Level of internal expertise

    • Externally collaborate


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

Scientific disciplines and development capabilities needed


Drug discovery and development is difficult and requires significant infrastructure and resources

Post-MarketingSurveillance

Drug Discovery

Preclinical

Clinical Trials

FDA Review

Scale-Up to Mfg.

~ 5,000 – 10,000

250

5

COMPOUNDS

ONE FDA-APPROVED DRUG

PRE-DISCOVERY

PHASE 3

PHASE 1

PHASE 2

NDA SUBMITTED

IND SUBMITTED

NUMBER OF VOLUNTEERS

20–100

100–500

1,000–5,000

0.5 – 2 YEARS

INDEFINITE

3 – 6 YEARS

6 – 7 YEARS

Drug discovery and development is difficult and requires 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”

Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006.


Increasing complexity of clinical trials
Increasing Complexity of Clinical Trials

During the last decade clinical trial designs andprocedures 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.


How are drugs and vaccines discovered and developed

Costs are recovered over a long period…

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.


And most marketed drugs don t recover their costs
…and most marketed drugs don’t recover their costs

Lifetime Sales Compared to Average R&D 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 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.

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.


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


How are drugs and vaccines discovered and developed

…..But as R&D spending increases, NME approvals have not.

No. of NMEs Approved

$ Billions R&D Spend

*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


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?


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
Roadmap for Developing an AIDS Vaccine

Solving the

Neutralizing

Antibody

Problem

Solving the

Problem of

How to Control

HIV Infection


Emerging challenges and continuing issues
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


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?


Trends in resource allocation to sg a cogs and r d in the pharmaceutical industry 1975 2007
Trends in resource allocation to SG&A, COGS and R&D in the pharmaceutical industry, 1975-2007


Federal and industry roles in research and development

Clinical Research

Clinical

Research

Translational Research

Translational

Research

Basic

Research

Basic Research

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, 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


Speed focus and collaboration will drive future success
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 earlyresearch 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



How are drugs and vaccines discovered and developed

Progression of HIV Infection and AIDS

Acute Infection

Symptom-free

AIDS


Drug discovery and development is difficult and requires significant infrastructure and resources1
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