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Promises and Perils of Translational Research at Academic Health Centers: The CCHMC Model. Timothy P. Cripe, MD, PhD Faculty Cross-Talk October 5, 2006. Public Mandate. It is no longer good enough to cure a mouse. Translational research is… “...moving a basic discovery

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Promises and perils of translational research at academic health centers the cchmc model

Promises and Perils of Translational Research at Academic Health Centers: The CCHMC Model

Timothy P. Cripe, MD, PhD

Faculty Cross-Talk

October 5, 2006


Public mandate

Public Mandate Health Centers:

It is no longer good enough

to cure a mouse.


Promises

Translational research is… Health Centers:

“...moving a basic discovery

into early clinical trials.”

Promises

  • J Kaiser, in

  • “Translational Research: A Cure for Medicine’s Ailments?”

  • Science 311:1852, 31 Mar 2006


Discovery Health Centers:

Development

Delivery


Discovery Health Centers:

Delivery

Development

Is it safe? Does it work? Can we make it better?


Translational research is a two way bridge

Laboratory Health Centers:

Clinic

Bench

Bedside

Petri Dish

Patient

Translational Research is a Two-Way Bridge



Peril 1 time and money
Peril #1: Time and Money Health Centers:


Time and money

Preclinical: 3-5 yrs, $3-5 million Health Centers:

Manufacturing: 1-2 yrs, $1-2 million

IND: 3-6 months, $0.5-1 million

Phase I: 1-2 yrs, $1-3 million

Phase II: 2-3 yrs, $3-6 million

Phase III: 3-4 yrs, $10-20 million

FDA: 1-3 yrs, $2-4 million

Time and Money

Source: http://www.wistechnology.com/article.php?id=377


Pharmaceutical drug development saganesque

15-20 years Health Centers:

Direct costs: $403 million

Add in marketing: $802 million

Some estimates up to $1.7 billion

Pharmaceutical Drug Development: Saganesque

“…billions and billions…”

From: DeMasi et al., J Health Economics 22:151, 2003


“…does anybody truly believe that academic translational research centers will be as efficient, let alone competitive, at developing drugs as pharma?”

“…investing in translational research is akin to building a bridge to nowhere.”

  • J Erickson, in

  • Commentary: “Translational Research and Drug Development”

  • Science 312:997, 19 May 2006


Is ahc translational research successful
Is AHC Translational Research Successful? research centers will be as efficient, let alone competitive, at developing drugs as pharma?”

Nature, Cell, Science,

JBC, JCI, J Exp Med

From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003


20 year follow up of promising basic science technology

Of those identified over 5 year period: research centers will be as efficient, let alone competitive, at developing drugs as pharma?”

1 in 4 led to published randomized trial

1 in 6 validated in positive trial

<1 in 10 entered routine clinical use

Only 1 deemed to have major impact

(ACE inhibitors)

20 Year Follow-up of Promising Basic Science Technology

From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003


From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003 research centers will be as efficient, let alone competitive, at developing drugs as pharma?”


Peril 2 regulatory hurdles
Peril #2: Regulatory Hurdles research centers will be as efficient, let alone competitive, at developing drugs as pharma?”


Human subject research

Extensive pre-clinical (laboratory) research precedes clinical trials

History has shown that safeguards are necessary to protect people in clinical trials

Safeguards are extensive

Enormous effort, time, costs underlie trials

Human Subject Research


Regulatory steps in translational research

cGMP clinical trials

IRB

TOX

SAC

RAC

IBC

IND

Regulatory Steps in Translational Research

IRB

Laboratory

Clinic


Levels of burden sponsor vs investigator
Levels of Burden: Sponsor vs. Investigator clinical trials

  • No IND

    • Fulfill PI level obligations (GCP)

  • Company-held IND

    • Fulfill PI level obligations (GCP)

  • Investigator-held, cross-referenced IND

    • Fulfill PI and Sponsor obligations (GCP)

  • Investigator-held IND

    • Manufacture product (GMP)

    • Conduct non-clinical studies (GLP)

    • Fulfill PI and Sponsor obligations (GCP)

      (Be the pharmaceutical company)



Hurdles for patient oriented translational clinical researchers

Training clinical trials

Extended

Requires scientist-clinician mentoring

Typically has been “on the job”

Funding

Especially for orphan diseases, childhood diseases!

Slow results (may take years for 1 trial)

Regulatory burdens

Fragmented infrastructure

Traditional metrics of success inadequate

Publications

Grants

Patient revenues

Hurdles for Patient-Oriented Translational Clinical Researchers

From: Nathan DG, J Clin Invest 115:795, 2005


Example hsv oncolysis for cancer

2001: Initial preclinical data clinical trials

ExampleHSV Oncolysis for Cancer

UV-Mutant HSV

Mutant HSV


Example hsv oncolysis for cancer1

2001: Clinical trial concept proposed clinical trials

2001-2004: More animal efficacy/safety

2004-2006: Regulatory/funding hurdles

Local

GCRC SAC, IBC, Radiation, IRB

National

NGVL, NIH RAC, FDA IND

ExampleHSV Oncolysis for Cancer



Why should ahcs conduct translational research

AHCs are birthplaces of ideas clinical trials

Lionshare of basic science research

Unburdened by company constraints

Tantalizing translational data needed to engage industry

AHCs can promote agendas with low market value

Orphan diseases

Pediatric diseases

Why should AHCs Conduct Translational Research?


CCHMC TRI NIH CTSA clinical trials

What’s an Institution to do?

  • Enhance scientific and clinical interactions

  • Build scientific infrastructure through grants program

  • Build clinical operations to facilitate complex and multidisciplinary translational and clinical trials

  • Provide support for complex regulatory help/oversight


Cchmc translational research initiative tri

Founded in 2001 clinical trials

Supported by clinical revenues

Two-tiered mission

To stimulate translational research via grants (financial support)

Pre-clinical and early phase clinical trials

Includes collection/analysis of biological samples

To create infrastructure (regulatory support)

New cores

Workshops for clinical/research interactions

Education

Annual symposium

Faculty scholar

Masters program for fellows

Translational Research Trials Office

CCHMC Translational Research Initiative (TRI):

Cripe et al. Acad Med 80:1012, 2005


Tri projects funded 2001 2004

Translational research projects clinical trials

31 projects

30 investigators

21 divisions/departments

$2.475 million

Cores

3 cores

Fanconi anemia cell repository

Human milk bank

Mouse genotoxicity

$250,000

Workshops/symposia/retreats

13

$39,000

TRI Projects Funded 2001-2004


Results first four years 30 investigators given 2 475 000

44 manuscripts clinical trials

18 extramural grants

Total direct costs: $27,691,304

7 patents

12 clinical trials launched

Results: First Four Years(30 Investigators given $2,475,000)


Trto office first five years

11 INDs (plus 2 in development) clinical trials

48 IRB-approved protocols

15 Therapeutic

33 Biologic/specimen collection

Utilized by 8 CCHMC divisions

Normal donor program for lab research

Blood (124)

G-CSF mobilized peripheral blood stem cells (86)

Bone marrow (173)

Umbilical cord blood (380)

TRTO Office: First Five Years


2001 trto human resources
2001 TRTO Human Resources clinical trials

Personnel Funding

100%

Institutional

Grants

2 staff


2006 trto human resources

Personnel Funding clinical trials

46%

54%

Institutional

Grants

2006 TRTO Human Resources

8 staff


In conclusion… clinical trials


Translational research mission impossible
Translational clinical trialsResearch:MissionImpossible?





Other ideas may also work
Other ideas may also work clinical trials



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