Janet Woodcock, MDDirector, Center for Drug Evaluation and ResearchFood and Drug Administration

Today’s Biomedical Innovation:“Lost in Translation”?

QB3 Entrepreneurs’ DiscussionUniversity of California, San FranciscoThursday, April 26, 2012

Will New Scientific Discoveries Revolutionize Treatment of Disease (Soon)?•Advances in both science and technology are providing unprecedented opportunities for new approaches to disease prevention, diagnosis and treatment•However, in some senses, the barriers to successful development have never been higher•New paradigms for evaluation of diagnostic and therapeutic interventions must be developed

– Faster – More efficient– But equally or more informative

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Drug Development• Currently takes more than 10 years and requires an

investment of over $1B to bring a single innovative drug to market

• Clinical investigation, premarket application, and postmarket stages are heavily regulated in most developed countries

• Ongoing concern about ability of the drug development enterprise to translate innovative science and bring needed therapies to market

• Ongoing concern about the ability, and willingness, of societies to pay for novel therapies

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Research and Development Process

3-6 YEARS 6-7 YEARS0.5-2

YEARS

PR

E-D

ISC

OV

ER

Y

DRUG DISCOVERY

PRECLINICAL

CLINICAL TRIALSFDA

REVIEW

LARGE SCALE

MFG

IND

SU

BM

ITT

ED

TO

FD

A

ND

A S

UB

MIT

TE

D T

O F

DA

PHASE 1 PHASE 2 PHASE 3

Number of Volunteers

20-100 100-500 1000-5000

PH

AS

E 4

: P

OS

T M

AR

KE

TIN

G S

UR

VE

ILLA

NC

E

5,000-10,000COMPOUNDS

250 5 ONEFDA-

APPROVEDDRUG

SOURCE: PhRMA 2008, Stages of Drug Development Process and attrition rate of compoundsas they travel through the drug development process over time.

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For 12 PhRMA companiesResearch Spending vs New Drugs Approved during the Period 1997-2011

$57,955

$81,708

$63,274

$85,841

$108,178

$88,285

$50,347

$35,970

$67,360

$45,675

$83,646

$33,229

5

10

8

11

1415

16

11

21

98

11

$-

$20,000

$40,000

$60,000

$80,000

$100,000

$120,000

AstraZe

neca

GlaxoSm

ithKlin

e

Sanofi

Roche Holding A

G

Pfizer In

c.

Johnson &

Johnso

n

Eli Li

lly &

Co

Abbott Laborat

ories

Merck &

Co Inc

Bristol-M

yers

Squibb Co

Novarti

s AG

Amgen In

c

Tota

l R&

D In

vest

men

t (in

$M

illio

ns)

0

5

10

15

20

25

Num

ber o

f Dru

gs A

ppro

ved

Total R&D Spending

Number of Drugs Approved

Source: InnoThink Center for Research in Biomedical Innovation; Thomson Reuters Fundamentals via FactSet Research Systems

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Private & PublicResearch and Development Spending

$11.3 $11.9 $12.7 $13.7$15.6

$17.8$20.5

$23.3

$27.9 $28.5 $28.5 $29.0 $29.3$30.6 $31.0

$15.2$16.9

$19.0$21.0

$22.7

$26.0

$29.8$31.0

$34.5$37.0

$39.9

$43.4

$47.9 $47.4$45.8

$49.4$47.6

$51.8

$56.1

$63.2 $63.7$65.3

$67.4

$27.1

$0

$10

$20

$30

$40

$50

$60

$70

$80

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Year

Tota

l R&

D In

vest

men

t (in

$Bi

llion

s)

Total NIH Budget

PhRMA Member Companies' R&D Expenditures

Entire Pharma Sector

Source: Burrill & Company, PhRMA, NIH Office of Budget

FDA NME Approvals• Basically stable output over long term (vs increased

investment in basic research and R&D)• Decline from late 1990s reflects primarily decrease in

submission of “me-too” drugs: now difficult to get on formulary

• FDA seeing increased novelty in applications over recent 5 year period; more “game-changing” therapies

• Possibly reflects adjustment of industry strategies• PDUFA program (currently up for re-authorization) ensures

that review times are relatively predicatable

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In 2011, CDER approved 30 NMEs,the highest total of NMEs approved in seven years

*The final number of NME Applications filed in 2011 is projected, pending final validation of the data and dependent outcome of 12 applications submitted in late 2011.

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CDER met review goal datesfor 97% of the new molecular entities approved in 2011Met PDUFA Target Dates

First Cycle Approval

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Innovation in drug approvals for 2011First in-Class Drugs

Approved First in the U.S.

Orphan Drug Approvals

Role of Regulatory Standards• Certainly some of the costs are driven by increased

expectations—over the last several decades--about evaluating the performance of the drug (both for safety and efficacy) before it goes on the market

• Even after an expenditure of $1B per successful drug, multiple important clinical questions remain unanswered (e.g. dose and regimen, use with other therapies, optimal duration of therapy, consequences of long-term use)

• Academic clinical community constantly clamors for more data to be generated premarket and postmarket

• Payer community has rising expectations—e.g., Europe

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Key Issues

• How to balance information needs of prescribers, patients and payers against desire for speedy access to better therapies (more effective, less toxic etc.) on the part of prescribers and patients?

• How to keep the biomedical innovation sector alive with a viable business model, but also keep new innovations affordable for society?

• How to translate the vast amount of new knowledge about human health and disease efficiently, rather than using the time-consuming, costly and inefficient methods currently in place?

• Is there a more prominent role for the academic biomedical sector?

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Can the Academic Biomedical Sector Become a more Integral Part of the DrugDevelopmentEcosystem?

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Background: A Very Long Time Ago

• Professors were engaged in drug discovery (and experimented upon themselves and their grad students)

• Industry commercialized discoveries• Industry largely unregulated

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Background: 1950-60s• Growth of mainstream (and other) pharmaceutical

houses• 1000’s of unstudied, possibly ineffective drugs on the

market• Start of a long period of seminal drug discoveries:

cardiovascular disease; infectious disease; cancer; psychiatric disorders

• Beginning of the requirement to show drug efficacy (1962)

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“Modern Era”• Huge pharmaceutical companies: massive “fully

integrated” drug discovery and development enterprises

• Academic focus on molecular biology of health and disease: “basic biomedical science”

• Outpouring of novel therapies and also x’s in a class (e.g., 17 NSAIDS)

• Society increasingly less impressed with novelty– Decreased tolerance of uncertainty– Regulators respond with more testing requirements– Cost effectiveness questions arise

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Now

• Pharmaceutical industry: progressively greater investment and diminished return

• Biotech: success, but can society afford the products?• Venture capital: fleeing medical products sector• Academia: 30 year investment in biomedical research

sector—will funding keep rising? What is the academic role in translational research?

• Regulators blamed for:– Current problems in drug development– Excess conservatism– Excess enthusiasm

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Current Government and Industry Roles in Pharmaceutical Research & Development

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Future: Opportunities for New Roles and Relationships to Improve Process • Pharmaceutical Sector Competencies

– Rigor – Medicinal chemistry– High throughput screening– Lead optimization– Manufacturing and scale up– Late phase development– Marketing and distribution

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Future: Potential Shift in Roles?

• Academic Strengths– Molecular biology of target; pathways;

pathogenesis– Animals and in vitro models and testing scenarios;

in depth disease understanding– Relationships with relevant patients– Proximity of patients and laboratory

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Future Role of Academia in Drug Discovery and Development• Partnering with industry in discovery and translation

of specific products or therapeutic areas• Research leading to new evaluative tools for

predicting, understanding and assessing the effects of medical products in the relevant species (people)

• Hubs for clinical trial networks that incorporate community practitioners and also have the capacity for integration of sophisticated bench science

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Role of Academia: Urgent Need for New Evaluative Tools

• Drug manufacturing and scale up– Multiple academic consortia working on this; poorly funded

• Safety evaluation: little changed in decades– Traditional empirical evaluation in animals– Human safety evaluation a “side effect” of efficacy evaluation

• Efficacy evaluation: Predicting and confirming efficacy still a huge challenge; generally still empirical– Affects academic efforts as well as industrial– Many late failures due to efficacy problems

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Discovery and Translation of Specific Innovations• “Academic based drug development”• Thousands of less common disorders that are not

subject to industrial development • Specific pathways or mechanisms that have been the

subject of extensive research in a particular laboratory

• Early bench to bedside translation– Proof of concept studies– Pharmacodynamic evaluations

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Streamlining the Bench to Bedside Transition• “Exploratory IND” guidance

– Tailor required toxicology studies to proposed investigations

– Can be significantly reduced for single dose or microdose trials, or brief administration

• Phase 1 trial cGMPs– Remove phase 1 clinical trial material from extensive

cGMP requirements in regulations– These were written for commercial products– Companion guidance: ability to use laboratory produced

material with specific safeguards

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Development of Evaluative Tools:A Tremendously Neglected Area

•Better science is needed to both predict and assess safety and efficacy of investigational products•Now: “Build an airplane and then see if it can fly” •Major causes of failure in Phase 3 clinical development

– Lack of effectiveness against placebo or active– Unexpected drug toxicity– Commercial non-viability (not better than existing therapy)

Evaluative Tools• Current drug development might be viewed as what physics

would be without engineering• Large amount of biochemical knowledge but few ways to

assess state of whole organism and impact of interventions at the organism level

• Most assessment tools are not standardized so limited ability to compare one experiment to another

• Little insight into sources of variability of treatment response, even current therapies

• As a result, most clinical development programs are “brute force” empirical efforts: extremely costly and time-consuming

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Safety Evaluation: Opportunities

• Routine rat or dog studies good for predicting safe first-in-human dose but not for understanding less common toxicities

• Structure Activity Relationships– FDA has collaborated to make some screening programs

available that correlate computer readable structural motifs with known animal or clinical adverse outcomes from FDA databases

– Opportunities to link structure with other assays that are becoming available and also do more extensive link to clinical data

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Safety Evaluation: Opportunities

• Systems biology approach to drug toxicity• Screens for off-target receptor binding• Gene expression in response to drug exposure: safety

pharmacogenomics• Cellular systems for assessing drug responses broadly• Human pharmacogenomics: not just drug metabolism

– Allelic variability in drug target– Uncommon alleles increasing risk of major drug toxicity

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Development of Biomarkers for Prediction of Safety or Efficacy• Many potential biomarkers discovered in academic

laboratories but never understood sufficiently for:– Use in drug development– Regulatory decision making

• FDA attempting to introduce more rigorous process as part of “Critical Path Initiative”

• FDA Guidance on “Drug Development Tools” qualification process: US and EU will work with groups on qualifying new tools for use in drug development

• A central role for academic scientists

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Predicting, Measuring, and Improving Efficacy

• New endpoints• New trial designs• Use of biomarkers to subset disease ( prognostic or

response predictors)– Jupitor trial (C-reactive protein; rosuvastatin)– Screening tumors for activating pathways– Known as “enrichment”, CDER guidance

• Use of patient-reported outcomes• Conducting natural history studies to understand

disease course—particularly in rare diseases

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New Endpoints

Foundation for the National Institutes of Health (FNIH) • Scientific work on endpoints and clinical trial designs

– FNIH and the Biomarkers Consortium are developing endpoints for clinical trials in skin infections and community acquired pneumonia

– Helps reduce uncertainty around using a new endpoint or trial design

– Includes academia, industry, IDSA, NIH, and FDA

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New Endpoints in Pain TrialsWhy ACTION?

Clinical studies, particularly efficacy trials, notoriously flawed for analgesic drug development

• Frequent failed studies with drugs known to be effective• Extremely small treatment effects even when successful• Multiple causes, e.g.:

Large placebo effectMissing dataStudy design flawsStudy analysis flawsInvestigator qualityFrequent use of foreign sites

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New Endpoints

Innovative clinical trial design to facilitate schizophrenia drug development…

• FDA and National Institute of Mental Health (NIMH)

• “MATRICS” clinical trial guidelines designed to facilitate novel compound development to treat cognitive impairment from schizophrenia (MATRICS) clinical trial guidelines for cognitive-enhancing drugs in schizophrenia

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Developing New Biomarkers and Patient Reported Outcomes Measures (PROs)

• C-Path Institute (nonprofit): submitted new biomarkers for drug induced kidney injury (data produced by a consortium); FDA and EMA accepted; undergoing clinical evaluation

• PROMIS (NIH PRO effort)• C-Path Institute: PROs for specific diseases for

qualification

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Quantitative Disease-Drug-Trial Models

DiseaseModel

Drug Model

TrialModel

BiologyNatural ProgressionPlaceboBiomarker-Outcome

BiologyNatural ProgressionPlaceboBiomarker-Outcome

PharmacologyEffectivenessSafety

Early-LatePreclinical-Healthy-Patient

PharmacologyEffectivenessSafety

Early-LatePreclinical-Healthy-Patient

Patient PopulationDrop-outCompliance

Patient PopulationDrop-outCompliance

FDA Data

DiverseExpertise

Physiology

Disease-drug-trial models are mathematical representations of the time course of biomarker-clinical outcomes, placebo effects, drug’s pharmacologic effects and trial execution characteristics for both the desired and undesired responses, and across experiments.

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Quantitative Disease-Trial Models:Alzheimer Disease

DiseaseModel

TrialModel

Natural ProgressionPlacebo ResponseNatural ProgressionPlacebo Response

Patient PopulationDrop-outPatient PopulationDrop-out

FDA Data

DiverseExpertise

Physiology

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Adaptive Design with Biomarkers

I-Spy 2: screening trial for investigational breast cancer drugs

• Biomarker Consortium--- public/private partnership: FDA / NIH / PhRMA companies

• Attempts to identify biomarker-defined response subgroups

• Adaptive design against standard-of-care

• Ability to screen multiple investigational agents in one trial

• Selected compounds could have rapid route to accelerated approval based on larger trial in responsive subgroup

Re-engineering the Clinical Research Enterprise

• Currently, clinical research is:– Extremely expensive– Unpleasant for most participants– Inefficient– Not totally reliable– Unavailable for the vast majority of patients (e.g., cancer patients)

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Clinical Research in Drug Development

• Unique clinical trial at multiple stages of development• New investigators, support personnel, unique CRFs• Long lead time to set up• Frequently slow recruitment, many sites fail to recruit

adequately• Lack of involvement of community practitioners, so that

available universe of patient limited, often sites are competing for patients for several protocols

• Rapid movement of clinical trials in drug development overseas

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How to Address Problem?• Consider clinical trial networks with the capacity to perform

multiple trials• Include community practitioners with appropriate logistical

support• Academic medical centers as hubs• Standardized CRF templates for much of data collection• Ultimately improve quality of data, involve community in

clinical research

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The Clinical Trials TransformationInitiative (CTTI)• Formed in 2008• FDA and Duke University - founding

members of a public-private partnership

• Members include stakeholders from government, industry, academia, patient and consumer representatives, clinical investigators, professional societies, and clinical research organizations

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CTTI Current Projects

• Improving the public interface for use of aggregate data in clinicaltrials.Gov

• Site metrics for study start up

• Building quality in

• Use of central IRB for multicenter clinical trials

Investigator

Sponsor Patient

IND SafetyReporting

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Summary• There are major problems with current drug development

paradigms• New scientific knowledge provides huge opportunity for

improvement• The biomedical research community should have a greater

role in many aspects of drug discovery and development• Future drug development must include many innovative

partnerships• The clinical research enterprise in the US must be

transformed