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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