NHLBI PACT WorkshopNHLBI�PACT�WorkshopObstacles�in�performing�translational�research�in��

pediatric populationspediatric�populations

Development�of�the�Tissue�Engineered�Vascular�Graft�for�Use�in�Congenital�Heart�Surgery:�A�Case�Study

Christopher�Breuer,�MDYale�University�School�of�Medicine

Disclosures: I have received grant supportDisclosures: I have received grant supportfrom ATRM, Gunze Ltd and Pall CorpI currently have business sitting before the FDA & NIH

Introduction:�Tissue�Engineering

Tissue�Engineering�II:�Cardiovascular�Tissue�Engineering

Fi t i St di d th L f F ithFirst� in�man�Studies�and�the�Leap�of�Faith

The road to perdition is paved with d i t tigood intentions

First�do�no�harm

Translational ResearchTranslational�Research

Background:�CONGENITAL�HEART�DISEASE

Single�Ventricle�Physiology

Extracardiac�Total�Cavopulmonary�Connection�(EC�TCPC)

Alexi�Meskishvili�et�al.�Eur�J�Cardiovasc�Surg�18�(2000)�690�695

Conduit�Limitations

Van�Son�Am�et�al.�J�Thorac�Cardiovasc�Surg�110�(1995)�1766�8

Classic Tissue Engineering ParadigmClassic Tissue Engineering Paradigm

BM�MNC

Serum

MNC

Serum

MNC

Centrifugation FicolFicol

RBC

Histology

Native IVCNative�IVC TE�IVC

In 2007 I set out in an attempt to obtain FDAapproval for a clinical trial evaluating the use ofapproval for a clinical trial evaluating the use ofTEVG in congenital heart surgery where theirgrowth potential could be used to its greatestgrowth potential could be used to its greatestadvantage.

Translational�Research

Bench Bedside

Problem�1

Lack of regulatory expertise in

ob e

Lack�of�regulatory�expertise�in�academia

Unfortunately…�one�size�doesn’t�fit�all

Potential SolutionsPotential�Solutions

• FDA website is an outstanding resource it it’sFDA�website�is�an�outstanding�resource…�it�it s�a�bit�daunting/overwhelming�for�a�neophyte

• FDA personnel can be tremendous• FDA�personnel�can�be�tremendous�resources…but�use�judiciously

C l di b i• Consults�are�outstanding…but�expensive

• There’s�no�substitute�for�taking�the�time�and�putting�in�the�effort�to�ultimately�teach�your�self

Problem�2

NIH�grant�funding�of�translational�hresearch

R01�HL105578� “An�exploratory�clinical�trial�evaluating�the�use�of�tissue�engineered�vascular�grafts�in�congenital�heart�surgery”

Not�Discussed� Triaged

Comparison of NIH to FDAComparison�of�NIH�to�FDA

• Mission focus�“enhance • Mission focus�”ensureMission�focus enhance�health”�

• Values�Efficacy

Mission�focus ensure�safety”

• Values�Safetyy

• Deals�w/�not�for�profit

• Information public

y

• Deals�w/�for�profit

• Information proprietaryInformation�public�domain

• Small�budget�projects

Information�proprietary

• Large�budget�projects

• Different Language/g p j

• Different�language/�jargon

Different�Language/�Jargon

j g

FDA

We�will�have�to�pull�ourselves�up�by�the�bootstraps

Potential�Solution:�Quality�data�and�baseball

Electronic�Medical�Record

Cost�of�Performing�Translational�Research

Turning weakness into a strength…Turning�weakness�into�a�strength…

Office�of�Orphan�Products

Office�of�Orphan�Products� Alternative�regulatory�pathway�designed�to�encourage�development�of�medical�drugs,�devices,�and�biologics�for�use�in�orphan�diseases.

1) L i d f t t l i it1)�Longer�period�of�patent�exclusivity2)�Limited�to�safety�testing�(efficacy�is�assumed�based�on�preclinical�studies)3)�May�charge�for�product�during�testing�phase

HUD 08�0196HUD�08 0196

HDE

Problem�3

Neovessel Formation

Speeding up the processSpeeding up the process…

In series

In parallel

Lessons learnedLessons�learned

• There�is�a�disconnect�between�the�NIH�and�FDA�that�is�both�valuable�and�an�obstacle�continued�efforts�to�address�these�issues�will�pay�great�dividends.��

Th i ifi t fi i l b i t f i di t i• The�significant�financial�barriers�to�performing�pediatric�research�can�be�greatly�reduced�using�the�orphan�pathway

• While�time�constraints�are�significant�barrier�initially�they�g y ytend�to�improve�with�time�and�experience