AIDS Drugs: The Development Pipeline (Jeffrey Sturchio)

8/7/2019 AIDS Drugs: The Development Pipeline (Jeffrey Sturchio)

1/24

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

1


2/24

2

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


3/24

How HIV/AIDS is Treated

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


4/24

4

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


5/24

5

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


6/24

6

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


7/24

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


8/24

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.


9/24

9

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


10/24

$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.


11/24

11

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


12/24

12

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.


13/24

13

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?


14/24

14

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


15/24

Roadmap for Developing anAIDS Vaccine

Solving theNeutralizingAntibodyProblem

Solving theProblem of

How to ControlHIV Infection


16/24

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

16


17/24

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?

17


18/24

Trends in resource allocation to SG&A, COGSand R&D

in the pharmaceutical industry, 1975-2007


19/24

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


20/24

20

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


21/24

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

21
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/


22/24

BACK-UPBACK-UP

22


23/24

Progression of HIV Infection andAIDS

AIDSAcute Infection Symptom-free


24/24

24

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

Documents

AIDS Drugs: The Development Pipeline (Jeffrey Sturchio)