economics of oncology drug development

Unresolved Issues in the Unresolved Issues in the Globalization of Clinical TrialsGlobalization of Clinical Trials

Robert M Califf MDRobert M Califf MD

Vice Chancellor for Clinical ResearchVice Chancellor for Clinical Research

Globalization of Clinical TrialsGlobalization of Clinical Trials

Current State Current State MoneyMoney

EthicsEthics

Cultural environmentCultural environment

Genetic variationGenetic variation

Envisioning a positive futureEnvisioning a positive future

• Since 2002, the number of FDA investigators outside the US has grown by 15% annually, while the number inside the US has declined by 5.5%.

• One-third of phase 3 trials of the 20 largest US pharmaceutical companies are being conducted solely outside the US.

• For those same firms and studies, a majority of study sites (13,521 of 24,206) are outside the US.

Source: Glickman, SW et al. NEJM 2009

The Globalization of Clinical Investigators

80% 77%70%

62% 57%

9% 10%11%

13%14%

5% 12% 13%19% 25% 29%

86%

9%

0%

25%

50%

75%

100%

1997 1999 2001 2003 2005 2007P

US-Based Western Europe Rest of WorldPercent of Total1572s Filed

Sources: Tufts CSDD

Growth in Numbers of ActiveFDA-Regulated Investigators

2001 2003 2006 5-yr Growth Rate

Most Recent 3-yr Growth

Rate

Russia 176 317 623 28.8% 25.3%

Poland 215 314 322 8.4% .8%

Brazil 139 296 292 16% -.5%

Costa Rica 12 20 22 12.9% 3.2%

Argentina 174 305 462 21.6% 14.8%

China 80 120 307 30.9% 36.8%

India 64 145 464 48.6% 47.4%

Sources: Tufts CSDD

The test of a first-rate intelligence is The test of a first-rate intelligence is the ability to hold two opposed ideas in the ability to hold two opposed ideas in the mind at the same time, and still the mind at the same time, and still retain the ability to function.retain the ability to function.

F. Scott FitzgeraldF. Scott Fitzgerald, , "The Crack-Up" (1936)"The Crack-Up" (1936)US novelist (1896 - 1940)US novelist (1896 - 1940)

http://www.quotationspage.com/quotes/F._Scott_Fitzgerald/

Creative TensionCreative Tension Globalization of clinical research is a very good Globalization of clinical research is a very good

thing for the US and for all of us in a flat worldthing for the US and for all of us in a flat worldWe need more evidence to guide effective practice We need more evidence to guide effective practice in the USin the US

So does every other country in the worldSo does every other country in the world

Driving globalization because of poor efficiency Driving globalization because of poor efficiency in the conduct of research in the US is a bad in the conduct of research in the US is a bad thing for the USthing for the US

By the way, the same thinking could be applied to By the way, the same thinking could be applied to any economically advantaged country that begins to any economically advantaged country that begins to think it is “above it all”think it is “above it all”

Dollars and Sense: Factors Pushing Dollars and Sense: Factors Pushing Clinical Research Out of the U.S.Clinical Research Out of the U.S.

Kevin Schulman, MDDirector, Health Sector Management Program

The Fuqua School of Business

Director, Center for Clinical and Genetic EconomicsDuke University Medical Center

American Federation for Medical Research (AFMR)

April 14, 2009

Globalization of Clinical Trials—The GoodGlobalization of Clinical Trials—The Good Larger sample sizes are neededLarger sample sizes are needed

Modest treatment effects predominateModest treatment effects predominate

Subgroups must be validatedSubgroups must be validated

Will become even more important in “personalized” or Will become even more important in “personalized” or “stratified” medicine“stratified” medicine

Competition spurs improvementCompetition spurs improvement

More research will be doneMore research will be done

Collaboration leads to shared learningCollaboration leads to shared learningPractice patternsPractice patterns

EthicsEthics

Will ensure transparency on results reportingWill ensure transparency on results reporting

Adequate sample sizes/study designs to understand genetic Adequate sample sizes/study designs to understand genetic heterogeneityheterogeneity

Globalization: A NecessityGlobalization: A Necessity

Proof of concept trials—there are Proof of concept trials—there are pharmacogenomic differencespharmacogenomic differences

Efficacy trials—the context of clinical practice Efficacy trials—the context of clinical practice mattersmatters

Effectiveness trials—the relative costs and Effectiveness trials—the relative costs and balance of risk and benefits are context balance of risk and benefits are context dependentdependent

The question is not whether we globalize, it is The question is not whether we globalize, it is why we do it, how we handle cultural why we do it, how we handle cultural differences and how we lump or split findings differences and how we lump or split findings

Economic Proposition to Industry From Economic Proposition to Industry From GlobalizationGlobalization

Return

0

$

$800 – $880 mil (2001)

$1 – $10 billion*

PatentPatent LaunchLaunchPatentPatent

ExpirationExpiration

Pre-LaunchPre-Launch

fall-off*fall-off*speed*speed*

duration*duration*

maximize area*maximize area*

Decrease costs or time

Potential local market opportunity

No requirement to match study populations to

target marketsROI

The Good– the US Needs to Wake Up!The Good– the US Needs to Wake Up! Rapid movement to moving clinical trials away Rapid movement to moving clinical trials away

from USfrom US

US is inferior in:US is inferior in:Study cost indexStudy cost index

Population indicators (tx naïve patients)Population indicators (tx naïve patients)

Business environmentBusiness environment

US is better, but losing ground quickly in:US is better, but losing ground quickly in:Clinical research personnel qualificationClinical research personnel qualification

Study site organizationStudy site organization

Thought leader quantityThought leader quantity

Image Source: http://www.pandora.ca/pictures21/900666.jpg

The Demise of EmpiresThe Demise of Empires Dominance at a point in timeDominance at a point in time

Arrogance about superiorityArrogance about superiority

Failure to pay attention to quality of workFailure to pay attention to quality of work

Leaders content to “ride the wave”Leaders content to “ride the wave”

Entrenched interests can buy stability through Entrenched interests can buy stability through controlling laws and regulationscontrolling laws and regulations

Inability to create or respond to innovationInability to create or respond to innovation

Cost of transactions exceeds cost of actually Cost of transactions exceeds cost of actually doing the work!doing the work!

Data gathered by the Tufts Center for the Study of Drug Development (Tufts CSDD)

>90% of all clinical trials delayed due to over-ambitious timelines and difficulty with patient enrollment

Top reasons for delays in trials: Protracted budget negotiationsSlow IRB review and approvalPoor patient recruitment and retention

Estimated 20% of PIs fail to enroll a single patient and 30% under-enroll in a given trial

Between 2000 and 2005 38% of PIs who participated in clinical trials in a given year did not return in a subsequent year through 2008

Up from 26% in previous 5 years

Patient Recruitment and RetentionPatient Recruitment and Retention

1999-2002 2003-2006

Percent Screened who were Randomized 75% 59%

Percent Randomized who Completed the

Study69% 48%

Screen : Complete 50% 25%

Source: Tufts CSDD

•Performance data on 57 phase II and III (across TAs) protocols provided by five pharmaceutical companies

8.7%10.5%

12.1%

-7.9%

6.5%

Number of UniqueProcedures

Frequency ofProcedures

Execution Burden Number ofEligibility Criteria

Ann

ual G

row

th R

ate

Compensation per Procedure

Protocol Designs More Complex and BurdensomeProtocol Designs More Complex and Burdensome

((2000-2006)2000-2006)

Sources: Tufts CSDD; Getz et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. American Journal of Therapeutics. 2008 15(5); 450 - 457

Represents 10,038 industry protocols; provided by Fast Track SystemsWork effort values based on Medicare’s RVU methodology

Performance ‘Impact’ of protocol complexityPerformance ‘Impact’ of protocol complexity

Compared US-based pivotal trial protocols executed 1999-2002 (lower complexity) and 2003-2006 (higher complexity):

Number of CRF pages rose to an average of 180 pages vs. 55

Controlling for treatment duration, cycle times increased substantially across all measures

Enrollment rates worsenedSource: Tufts CSDD

Cycle Time MetricsCycle Time Metrics

115 120

413460

129 143

714780

Protocol Ready toFPFV

Protocol Ready toDrug Available

Protocol Ready toLPLV

Protocol Ready toData Lock

1999-2002 2003-2006

12% – 20% Increase

69% - 75% Increase

Med

ian

Day

s Ela

psed

Source: Tufts CSDD

Clinical Trial Cost EstimatesClinical Trial Cost Estimates

$0$50

$100$150$200$250$300$350$400$450

To talCo ord in ating CenterS ite Paym entsOth er

Full Cost Industry

Streamlined Industry

More Streamlined

$ In US 2007 Millions

Source: Roses AD. Nature 2000;405:857-865.

Pharmacogenomics

Randomized Trial of Genotype-Guided Dosing of Warfarin Therapy:Influence of Genotype on Warfarin Dose?

Genotype(N = 188)

Prevalence % Enzyme Activity

S/R Warfarin(mg/L)

Daily Doses(mg)

Clearance/LBW

(ml/min/kg)

2C9 *1/*1 64% 100% 0.45 (0.11)

5(2.5)

0.065 (0.025)

2C9 *1/*2*2/*2

21% 50-70% 0.69(0.28)

3(1.5)

0.041 (0.021)

2C9 *1/*3*2/*3 *3/*3

15% 10% 1.43(0.63)

2(1.0)

0.020 (0.011)

Herman et al, The Pharmacogenomics J 4:1-10. 2005

McClain et al, ACMG Presentation, October 30, 2006 (In Press)(From L. Lesko)

Randomized Trial of Genotype-Guided Dosing of Warfarin TherapyBoxplots of distribution of warfarin dose byCYP2C9 and VKORC1 genotype

Sconce et al. Blood 2005; 106:2329

-NEJM 360; 2009

Cytochrome P-450 Polymorphisms and Clopidogrel Response

-NEJM 360; 2009

GENEVA, SWITZERLAND—World Health Organization officials expressed disappointment Monday at the group's finding that, despite the enormous efforts of doctors, rescue workers and other medical

professionals worldwide, the global death rate remains constant at 100 percent.Death, a metabolic affliction causing total shutdown of all life functions, has long been considered

humanity's number one health concern. Responsible for 100 percent of all recorded fatalities worldwide, the condition has no cure.

"I was really hoping, what with all those new radiology treatments, rescue helicopters, aerobics TV shows and what have you, that we might at least make a dent in it this year," WHO Director General Dr. Gernst Bladt said. "Unfortunately, it would appear that the death rate remains constant and total, as it

has inviolably since the dawn of time."

The Good--More Research will be DoneThe Good--More Research will be Done

Broader sources of fundingBroader sources of fundingMany governments now giving tax breaks for Many governments now giving tax breaks for industry funded researchindustry funded research

Do the research where costs are lessDo the research where costs are less

Do the research where barriers to trial initiation Do the research where barriers to trial initiation are lessare less

ACC/AHA Clinical Practice Guidelines

19.0%

44.9%

36.3% LoE A

LoE B

LoE C

ACC/AHA Guidelines: Level of Evidence of Recommendations

0%

10%

20%

30%

40%

50%

60%

70%

A B C A B C A B C A B C A B C A B CAtrial

Fibrillation (2001-2006)

Heart Failure

(2001-2006)

Stable Angina

(1999-2002)

Unstable Angina

(2000-2007)

PCI (2001-2005)

Pacemaker (1998-2002)

ACC/AHA Guidelines: More GuidelinesNo Improvement in Proportion with High Quality!

The BadThe Bad

Differences in practices can be found as a Differences in practices can be found as a function of geographyfunction of geography

Differences in outcomes can be found as a Differences in outcomes can be found as a function of geographyfunction of geography

Differences in treatment effect can be found as Differences in treatment effect can be found as a function of geographya function of geography

Andrzej Budaj for the GRACE Investigators

Postgraduate Medical School, Grochowski Hospital, Warsaw Poland

Current Practices in ACS Care

USA vs Rest of GRACE

In-hospital ManagementAll ACS

USA Rest of GRACE

AA (%) 95 95

B-blockers (%) 88 82

ACE-I (%) 61 66

Statins (%) 65 66

B-blockers iv (%) 27 9

ARB (%) 7 5

Other lipid lowering (%) 8 3

Temporal trends USA vs Rest of GRACE

4.24.8

4.04.7

4.44.9

6.35.7

2

3

4

5

6

7

8

2000 2002 2004 2006

USARest of GRACE

% Death in hospitalAll ACS

9808LB11, 9808LB11, 3838

Death and/or MI at 30 Days

FemaleFemale

MaleMale

0.50.5 11 1.51.5

Placebo EptifibatideTotal n

16.88 13.896103

13.68 14.88

3357

PlaceboBetter

EptifibatideBetter

PT-E2-7PT-E2-7

9808LB11, 9808LB11, 3939

Death and/or MI

FemaleFemaleMaleMale




0.20.2 11 55

Placebo Eptifibatide Total n16.16 12.35 249912.89 10.57 132816.03 13.03 254212.10 15.52 115420.35 20.43 81419.05 21.78 72721.43 16.39 2485.63 15.58 148

PlaceboBetter

EptifibatideBetter

NA

WE

EE

LA

PT-E2-8PT-E2-8

9808LB11, 9808LB11, 4040

Timing of Angiography

0

25

50

75

100

72Hours

7Days

30Days

72Hours

7Days

30Days

72Hours

7Days

30Days

72Hours

7Days

30Days

72Hours

7Days

30Days

%

MaleFemale

Overall North America

Western Europe

Eastern Europe

Latin America

PT-C-17PT-C-17

Study Undertaken by FDA Study Undertaken by FDA statisticians to evaluate statisticians to evaluate possibility of systematic possibility of systematic

regional differencesregional differences Major cardiovascular outcome Major cardiovascular outcome

studies evaluated over the last 10 studies evaluated over the last 10 yearsyears

Overall study result statistically Overall study result statistically positive, ie. demonstrated overall positive, ie. demonstrated overall effecteffect

Region never pre-specified as a Region never pre-specified as a factor to be evaluated statisticallyfactor to be evaluated statistically

16 independent studies16 independent studies

difference of log-hazard ratios

Study % US

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

31145227394451964373884974107411912313291417159016

Estimates and confidence intervals for difference between US and Non-US treatment effects for each

study

J. Lawrence

In 13 of 16 , US log hazard above 0

A figureFrom the label

External ValidityExternal Validity

Internal ValidityInternal Validity

Goal

X

Article cites numerous examples of trials, which produce Article cites numerous examples of trials, which produce parameter estimates of questionable value to Western parameter estimates of questionable value to Western European decision makers and highlights differences European decision makers and highlights differences between emerging regions and Western Europeans, which between emerging regions and Western Europeans, which suggest the two are mutually incomparable.suggest the two are mutually incomparable.

Proposed that these differences may confound study Proposed that these differences may confound study outcomes, decision-making parameter estimates and data outcomes, decision-making parameter estimates and data pertaining to the incidence of adverse drug interactionspertaining to the incidence of adverse drug interactions

Further research should be undertaken in order to explore Further research should be undertaken in order to explore the relationship between geographical variance and the relationship between geographical variance and external validity, particularly where safety data derived external validity, particularly where safety data derived from relatively drug naïve regions are assumed to pertain from relatively drug naïve regions are assumed to pertain to a maximally treated populations elsewhere in the worldto a maximally treated populations elsewhere in the world

Source: Wathal. Outsourcing Clinical Trials www.samedanltd.com

Extrinsic factors such as medical practice, disease definition and Extrinsic factors such as medical practice, disease definition and study population may influence applicability of foreign data to an study population may influence applicability of foreign data to an EU settingEU setting

Global drug development doesn’t necessarily support approval of Global drug development doesn’t necessarily support approval of unrestricted indications in an EU populationunrestricted indications in an EU population

Consider and discuss possible influence of extrinsic Consider and discuss possible influence of extrinsic factors on interpretation of results and wording of factors on interpretation of results and wording of indicationsindications

In depth, prospective analysis of potential ethnic factors when In depth, prospective analysis of potential ethnic factors when conducting a clinical trial in a certain region.conducting a clinical trial in a certain region.

Depending on the outcome of analyses can be Depending on the outcome of analyses can be decided whether certain clinical trials conducted in a decided whether certain clinical trials conducted in a specific area of the world would be relevant to EU specific area of the world would be relevant to EU setting or if there are reasons to perform additional setting or if there are reasons to perform additional clinical trials within the EUclinical trials within the EU

Source: European Medicines Agency, Pre-Authorization Evaluation of Medicines for Human Use. Feb. 19, 2009

Verification at time of evaluation of marketing Verification at time of evaluation of marketing authorization application that trials have been authorization application that trials have been conducted in accordance with GCP and ethical conducted in accordance with GCP and ethical standardsstandards

Greater transparency of this process and Greater transparency of this process and its outcome should be described in the its outcome should be described in the European Public Assessment Report (EPAR)European Public Assessment Report (EPAR)

Increased GCP inspection including further Increased GCP inspection including further extension of GCP policy on increasing numbers of extension of GCP policy on increasing numbers of routine inspections as part of the need for greater routine inspections as part of the need for greater supervision of the conduct and ethical standards of supervision of the conduct and ethical standards of clinical trials performed outside the EEAclinical trials performed outside the EEA

Source: European Medicines Agency, EMEA strategy paper: acceptance of clinical trials conducted in the third countries, for evaluation in Marketing Authorization Applications. Feb. 5, 2008

Source: Reed SD, Drug Information Journal, 2007

The UglyThe Ugly

Differences in reported adverse events can be Differences in reported adverse events can be found in different countriesfound in different countries

Is there a relationship between relative financial Is there a relationship between relative financial incentive and lower rates of side effects?incentive and lower rates of side effects?

Differences in adherence can be found in Differences in adherence can be found in different countriesdifferent countries

Is there a relationship between lack of access to Is there a relationship between lack of access to health care outside of the trial and adherence?health care outside of the trial and adherence?

The UglyThe Ugly

Non-Non-AdherencAdherencee

WithdrawaWithdrawal:AE’sl:AE’s

WithdrawaWithdrawal: Subject l: Subject preferencepreference

Withdrew Withdrew ConsentConsent

UKUK 39.7%39.7% 12%12% 17%17% 5555USUS 35.5%35.5% 7%7% 16%16% 166166Poland Poland 14.8%14.8% 2%2% 9%9% 22ChinaChina 6.1%6.1% 5%5% 5%5% 11ArgentinaArgentina 13.6%13.6% 2%2% 8%8% 11

The ObsceneThe Obscene

When the per patient reimbursement exceeds When the per patient reimbursement exceeds reasonable levels, the human experimentation reasonable levels, the human experimentation entrepreneurs will be tempted entrepreneurs will be tempted

When the FDA cannot inspect, the cheaters will When the FDA cannot inspect, the cheaters will figure out how to get the data looking real figure out how to get the data looking real good!good!

Source: http://www.tampabay.com/news/business/article934677.ece

Source: http://www.tampabay.com/news/business/article934633.ece

Source: http://www.tampabay.com/opinion/essays/article934654.ece

Ethical Concerns in clinical trials in India: an investigation

• Lapatinib, GlaxoSmithKline– The majority of breast cancer patients in India cannot

afford proper treatment. This trial required seriously ill patients who had not received treatment for their condition.

– Their economic vulnerability forces patients in India to take part in trials in order to get access to treatment and to disregard the potential risks that participating in clinical trials entails. By carrying out this clinical trial in India GlaxoSmithKline (GSK) took advantage of the vulnerable position of breast cancer patients.

Source: Srinivasan S, et al. Ethical concerns in clinical trials in India: an investigation. Center for Studies in Ethics and Rights, Mumbai, India. Feb. 2009

• Risperidone, Johnson & Johnson– Patients in trial were suffering from an acute

attack of a psychiatric condition that would have caused them much distress.

– They were harmed because they were taken off all treatment before they were put on either the active drug or a placebo.

– Those on the placebo were also harmed because they were deprived of an effective treatment



• Quetiapine fumurate extended release, AstraZeneca– These two placebo-controlled trials of

quetiapine were conducted on patients with schizophrenia. An immediate release formulation of the drug had already been approved and these trials were of an extended release version of the drug.

– A patient in one of the quetiapine trials committed suicide after 173 days of being on placebo.



Factors Pulling Research Offshore

• Cost: cost per patient may be 1/10 the cost in the US (Garnier, JP).

• Availability: untreated or under-treated patients may speed recruitment of patients to clinical trials reducing the time costs of research.

• Regulations: local processes may be more variable (and potentially less restrictive) than in the US.

Source: Garnier JP. Rebuilding the R&D engine in big pharmacy. Harv Bus Rev 2008;86:68-76.

Factors Pushing Research Offshore

• Costs (Clinical Care)• Costs (Administrative)

• Systems that developed to govern single site studies are inefficient in oversight of multicenter, multinational studies

• IRB (redundant site level process)• Contracting (redundant site level process)• Compliance (research as a potential criminal

issue)

Administrative Barriers

Source: Dilts, DM et al. Journal of Clinical Oncology Oct. 2006

CommentsEvent Time

IRB Approval Timeline for a Focus Group discussing Health Insurance with Latinos

Oct 2007

Feb 2008

Apr 2008

Oct 2008

Jan 2009

Aug 2007

Aug-Sep 2007

May-Sep 2008

Rewritten study submitted to IRB

Continued negotiations between local cultural center and IRB

Local cultural center requests major changes to study

Initial study approved by IRB

Study rewritten and submitted as expedited

Discussions with IRB about rejection of exempt status

Study Submitted to IRB as Exempt

IRB requested additional changes

Incorporate relevant cultural concerns in initial study design

IRB requested extensive changes

Focus groups may not qualify for IRB exempt status

IRB rejected exempt status

Final Study Approved

Contracting for Clinical Research

“…the system would be better served if there were universally accepted

contractual language …Such language would help safeguard the

integrity of the research process.”

-JEFFREY M. DRAZENEditor-in-Chief, New England Journal of Medicine

Source: Drazen, JM. NEJM Oct. 24, 2002

(1) I am familiar with, and will comply with, applicable federal regulations and guidance for the protection of human subjects: HHS regulations at 45 FR 46 and associated guidance; FDA regulations at 21 CFR Parts 50, 54, 56, 312, 314, 601, 812, and 814 and associated guidance; the HIPAA privacy regulations at 45 CFR Parts 160 and 164 and associated guidance; the DUHS Federal-Wide Assurance; and relevant institutional policies and procedures for the protection of human research subjects.

Source: DUHS Principal Investigator Agreement form. Version 6/25/08

Source: Glickman, SW et al. NEJM 2009.

Selection of Patients in Multinational Trials

• Problem: Research in communities that are not intended to be major markets for the products under testing can be ethically problematic

• Solutions– Sponsors should describe how trial populations match

intended markets– Create target enrollment according to region on the basis

of intended use of product, similar to target enrollment of women and minorities


Transparency of Clinical Trial Results in Developing Countries

• Problem: Protection of publication rights and access to trial data for investigators is necessary to preserve the integrity of research

• Solutions– Publish all data regardless of research location, and

reinforce requirements according to FDA Amendments Act of 2007

– Preserve publication rights globally through legal agreements at onset of trial

– Create trial leadership that incorporates representatives of countries involved in study


Regulatory Oversight of International Clinical Research

• Problem: Regulatory agencies have little information on trials conducted outside their countries

• Solutions– Mechanism for sharing regulatory oversight among

government agencies worldwide– Public registry of IRBs and inventory of country-specific

provisions for ethical oversight– Comprehensive study of the globalization of clinical

research by IOM or WHO– Central statistical monitoring system to find unusual data

patterns suspicious for fraud


Training and Experience of Clinical Investigators

• Problem: Investigators in developing countries are typically less experienced than investigators in developed countries

• Solutions– Formal training programs for clinical research for

investigators in developing countries to expand global clinical research leadership capacity and improve collaboration worldwide

– Mechanism for tracking investigators who are trained to conduct clinical trials and those who have been prohibited from conducting trials


Genomic Information in Drug Development

• Problem: Lack of pharmacogenomic data for subjects limits confidence in generalizability of results

• Solutions– Expand FDA Voluntary Genomic Data Submissions

program to international regulatory agencies– Develop global data warehousing and data analysis

capabilities


IRB Quality and Inefficiency

• Problem: Redundancy in review process may harm patient safety by requiring diversion of effort to unnecessary procedures and practices

• Solutions– Greater use of centralized IRBs (eg, Central IRB

Initiative, European Union Clinical Trials Directive)– Mutual acceptance of proposal review in consortia (eg,

Biomedical Research Alliance of New York)– Streamlined best practices to reduce unnecessary

work for investigators (eg, Clinical Trials Transformation Initiative)


Payment Compliance• Problem: Increased costs and delays in payment

for research subjects divert financial support from research to administration and make research less attractive to investigators because of risk of criminal penalties

• Solutions– Establish nonpunitive mechanism for reconciliation of

payment– Expand mechanisms to pay for usual care services (eg,

within Medicare and Medicaid)


Commercial Contracts• Problem: Variety of contracting practices

brings complexity and delays to research• Solutions

– Adopt standard contract language for clinical research agreements


Confidentiality Agreements inCommercial Contracts

• Problem: Confidentiality agreements reduce the transparency and efficiency of clinical research

• Solutions– Adopt standard confidentiality language for clinical

research agreements


A collaborative effort to find solutions In light of these issues the U.S. FDA’s Office of

Critical Path Programs and Duke University joined together as founding members of a public-private partnership:

The Clinical Trials Transformation Initiative (CTTI)

All stakeholders are involved in this initiative including government, industry, academia, patient advocates, clinical investigators, professional societies, and others

Mission

To identify practices that through broad adoption will increase the quality and efficiency of clinical trials

Scope

CTTI will conduct projects in support of its mission to identify practices that will increase the quality and efficiency of clinical trials

“Quality” - the ability to effectively answer the intended question about the benefits and risks of a medical product (therapeutic or diagnostic) or procedure, while assuring protection of human subjects

Scope (continued)

CTTI will generate evidence about how to improve the design and execution of clinical trials

Projects about design will address principles generally applicable to clinical trials to assure that they are fit to accomplish their intended purpose.

Scope (continued)

While CTTI focuses on clinical trials, it may study other types of clinical research (e.g., registries) that can provide data to regulatory agencies.

Although CTTI will concentrate initially on the design and conduct of clinical trials in the United States, it seeks to identify practice improvements that can be applied internationally.

Executive Committee FDA: (Rachel Behrman, OC, Co-chair; Bob Temple,

CDER, Bram Zuckerman, CDRH) Duke: (Rob Califf, Co-chair) NIH liaison: (Amy Patterson) Industry: (Glenn Gormley, Jay Siegel, Susan Alpert,

Alberto Grignolo) Academia: (David DeMets) Patient representative: (Nancy Roach) At-large representative: (Ken Getz) Non-US regulatory liaison: (Hans-Georg Eichler, EMEA) Steering Committee co-chairs, ex officio (James

Ferguson, Briggs Morrison)

Member Organizations Category # organizationsPharmaceutical companies 7Clinical research organizations 7Academic institutions 7Professional societies 7Device companies 6Biotechnology companies 5Government 4 (FDA, CMS, NIH, OHRP)Clinical investigator groups 3Trade organizations 3Patient representatives 2 (TBD)Private equity firm 1Regulatory law firm 1

*Began recruiting members May 2008

Projects Priority areas defined by Executive Committee:

Design principlesData quality and quantity (including monitoring)Study start-upAdverse event reporting

Information about the process for submission, review, and approval of projects available at CTTI Web site:

www.trialstransformation.org/projects

http://www.trialstransformation.org/projects

http://www.trialstransformation.org/projects

Life Expectancy at Birth: Developed and Developing Countries, 1955-2002

Source: World Health Report 2003

economics of oncology drug development

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