Company-Sponsored Research Agreements: Company-Sponsored Research Agreements:

What Academic Laboratories Should Know Before What Academic Laboratories Should Know Before AcceptingAccepting

Presented by John W. Ludlow, Ph.D.Presented by John W. Ludlow, Ph.D.

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Company-Sponsored Research Agreements: Company-Sponsored Research Agreements: What Academic Laboratories Should Know Before AcceptingWhat Academic Laboratories Should Know Before Accepting

Biotech companies continue to look for cost-effective ways to Biotech companies continue to look for cost-effective ways to conduct studies in support of product development conduct studies in support of product development

Academic laboratories are a practical solution due to their Academic laboratories are a practical solution due to their lower cost of services compared to commercial Contract lower cost of services compared to commercial Contract Research Organizations (CRO)Research Organizations (CRO)

This is especially true for studies supporting development of This is especially true for studies supporting development of tissue engineered and regenerative medicine products, as tissue engineered and regenerative medicine products, as they often require unique services which are typically outside they often require unique services which are typically outside the usual CRO cataloguethe usual CRO catalogue

Company-sponsored research agreements can serve Company-sponsored research agreements can serve academic researchers well, given the downward trend of the academic researchers well, given the downward trend of the funding rate at NIH, NSF, and private foundations, due to funding rate at NIH, NSF, and private foundations, due to increasing applications coupled with stagnant budgetsincreasing applications coupled with stagnant budgets

Presentation GoalsPresentation Goals

1.1. Provide insight into the Provide insight into the regulated environment under regulated environment under which biotech companies are which biotech companies are required to operaterequired to operate

2.2. Better position the academic Better position the academic laboratory so that the needs of laboratory so that the needs of the company sponsor can be the company sponsor can be metmet

Areas of emphasis for academic laboratory positioning are Areas of emphasis for academic laboratory positioning are highlighted in highlighted in yellowyellow

1. Introduction1. Introduction

• Defining TE/RM productsDefining TE/RM products

• Product evaluationProduct evaluation

2. Requirements for study conduct2. Requirements for study conduct

• Protocol developmentProtocol development

• Good Laboratory Practices (GLP)Good Laboratory Practices (GLP)

3. Sponsor expectations and awardee responsibilities3. Sponsor expectations and awardee responsibilities

• Project controlProject control

• Intellectual property and publication rightsIntellectual property and publication rights

4. Assets appealing to commercial sponsors4. Assets appealing to commercial sponsors

5. Suggested resources5. Suggested resources

6. Summary and closing remarks6. Summary and closing remarks

Presentation OutlinePresentation Outline

Defining TE/RM products Defining TE/RM products

Why use TE/RM products as the example? Why use TE/RM products as the example?

• Tissue Engineered/Regenerative Medicine (TE/RM) Tissue Engineered/Regenerative Medicine (TE/RM) products are relatively new with respect to products are relatively new with respect to commercial development of treatment strategiescommercial development of treatment strategies

• Regulatory agencies (ie: FDA) are still developing Regulatory agencies (ie: FDA) are still developing guidelinesguidelines

• CROs may be at a disadvantage with respect to the CROs may be at a disadvantage with respect to the services they can provide for TE/RM productsservices they can provide for TE/RM products

• These factors help to position academic laboratories These factors help to position academic laboratories as the “go-to” place to have critical work performed as the “go-to” place to have critical work performed for biotech companies developing TE/RM products, for biotech companies developing TE/RM products, provided certain expectations are met by the provided certain expectations are met by the academic laboratoryacademic laboratory

Defining TE/RM productsDefining TE/RM products• Tissue Engineering/Regenerative Medicine Tissue Engineering/Regenerative Medicine

(TE/RM) refers to a broad range of emerging (TE/RM) refers to a broad range of emerging technologies that employ cells, biomaterials or technologies that employ cells, biomaterials or cell/biomaterial combinations (referred to as cell/biomaterial combinations (referred to as “constructs”) to reconstitute functional tissue “constructs”) to reconstitute functional tissue or organ-like structures or organ-like structures ex vivoex vivo (neo-organs) (neo-organs) and/or to catalyze organogenesis and/or to catalyze organogenesis de novode novo by by leveraging the body’s innate ability to leveraging the body’s innate ability to regenerate itselfregenerate itself

• Tissue engineering and regenerative medicine Tissue engineering and regenerative medicine are two terms often used synonymouslyare two terms often used synonymously

• A subtle difference between these terms may A subtle difference between these terms may be that tissue engineering emphasizes the be that tissue engineering emphasizes the biomaterials and engineering components, biomaterials and engineering components, while regenerative medicine accentuates the while regenerative medicine accentuates the cellular contributioncellular contribution

Defining TE/RM products - CellsDefining TE/RM products - Cells1.1. Cell populations with application in TE/RM may be Cell populations with application in TE/RM may be

broadly divided into two categories: broadly divided into two categories: • Stem and progenitor cellsStem and progenitor cells• Committed cell typesCommitted cell types

2.2. The cell is the primary Active Biological Ingredient (ABI) The cell is the primary Active Biological Ingredient (ABI)

3.3. Mechanisms of action includeMechanisms of action include

• Leverage the “classical” properties of stem cells Leverage the “classical” properties of stem cells (self-renewal, multi-lineage differentiation potential) (self-renewal, multi-lineage differentiation potential)

• Action-at-a-distance paracrine signaling pathways, whereby native stem Action-at-a-distance paracrine signaling pathways, whereby native stem and progenitor cell populations are recruitedand progenitor cell populations are recruited• Release cytokines and growth factors that promote angiogenesis and Release cytokines and growth factors that promote angiogenesis and

neo-vascularization, modulate inflammatory, fibrotic and apoptotic cascades neo-vascularization, modulate inflammatory, fibrotic and apoptotic cascades and interfere with the onset of pathology while promoting repair and and interfere with the onset of pathology while promoting repair and regeneration regeneration • Niche-specific directed differentiation towards defined developmental Niche-specific directed differentiation towards defined developmental

lineages as regulated by contextual signaling cues derived from the lineages as regulated by contextual signaling cues derived from the surrounding tissue or organ parenchyma surrounding tissue or organ parenchyma

Defining TE/RM products - BiomaterialsDefining TE/RM products - Biomaterials

• The most straightforward classification of The most straightforward classification of biomaterials is based on source, which may be of biomaterials is based on source, which may be of natural or synthetic originnatural or synthetic origin

• Examples of naturally occurring biomaterials Examples of naturally occurring biomaterials include gelatin, fibrin, hyaluronic acid (HA), include gelatin, fibrin, hyaluronic acid (HA), chitosan, silk, collagen and alginatechitosan, silk, collagen and alginate

• Such naturally derived biomaterials are typically Such naturally derived biomaterials are typically well tolerated upon introduction within the body well tolerated upon introduction within the body and tend to reflect properties of native and tend to reflect properties of native extracellular matrix (ECM) well extracellular matrix (ECM) well

• Naturally sourced biomaterials are potentially Naturally sourced biomaterials are potentially problematic, presenting difficulties in sourcing, problematic, presenting difficulties in sourcing, quality control, reliability and reproducibility quality control, reliability and reproducibility across lot to lotacross lot to lot

• Synthetic biomaterials such as poly-Synthetic biomaterials such as poly-coco-glycolic -glycolic acid (PGA), poly-lactic-acid (PGA), poly-lactic-coco-glycolic acid (PLGA) -glycolic acid (PLGA) and poly-L-lactic acid (PLLA), offer better and poly-L-lactic acid (PLLA), offer better reliability and reproducibilityreliability and reproducibility

Defining TE/RM products - ConstructDefining TE/RM products - Construct1.1. Any TE/RM product or product candidate Any TE/RM product or product candidate

incorporating a cellular ABI may be defined as a bi-incorporating a cellular ABI may be defined as a bi-component “construct” or combination product component “construct” or combination product composed of:composed of:

• Cellular ABI Cellular ABI • Biomaterial or scaffoldBiomaterial or scaffold

2.2. As currently understood, the role of biomaterials As currently understood, the role of biomaterials within today’s TE/RM products may include:within today’s TE/RM products may include:

• Providing space for tissue repair and Providing space for tissue repair and regeneration regeneration • Providing a foundation for the expansion and Providing a foundation for the expansion and

delivery of therapeutic exogenous cell delivery of therapeutic exogenous cell populationspopulations• Serving as a framework for the deposition of Serving as a framework for the deposition of

extracellular matrix and paracrine signaling extracellular matrix and paracrine signaling factorsfactors• Providing a foundation for the regeneration of Providing a foundation for the regeneration of

neo-tissue and neo-organs in a manner neo-tissue and neo-organs in a manner appropriate to the local micro-environmentappropriate to the local micro-environment

Product EvaluationProduct Evaluation1.1. There is an established pathway for pharmaceutical compound development and There is an established pathway for pharmaceutical compound development and

review by the FDA. Developers of TE/RM products have to improvise certain parts review by the FDA. Developers of TE/RM products have to improvise certain parts of this established pathway, especially when it comes to ADME Tox testingof this established pathway, especially when it comes to ADME Tox testing

•AdsorptionAdsorption

•DistributionDistribution

•MetabolismMetabolism

•ExcretionExcretion

•ToxicityToxicity

2.2. Both Both in vitroin vitro and and in vivoin vivo animal testing is required before the FDA will allow any animal testing is required before the FDA will allow any medicinal product to be tested in humans. These studies need to be well defined, medicinal product to be tested in humans. These studies need to be well defined, controlled, and monitoredcontrolled, and monitored

3.3. TE/RM products rarely, if ever, lend themselves to such pharmacologic and TE/RM products rarely, if ever, lend themselves to such pharmacologic and toxicologic studies as the ‘small molecule’ drug compound development programs toxicologic studies as the ‘small molecule’ drug compound development programs havehave

Product EvaluationProduct Evaluation1.1. TE/RM product parameters to be tested TE/RM product parameters to be tested in vitroin vitro often include cell viability, often include cell viability,

morphology, phenotype, function, cryopreservation, biocompatabilitymorphology, phenotype, function, cryopreservation, biocompatability

2.2. Biomarker analysis of TE/RM products is the best correlation to the established Biomarker analysis of TE/RM products is the best correlation to the established regulatory path of ADMET testing which pharmaceutical compounds go through, regulatory path of ADMET testing which pharmaceutical compounds go through, and may include:and may include:

• Multiplex cytokine array and secretome analysis to address function, Multiplex cytokine array and secretome analysis to address function, potency, and fitness of usepotency, and fitness of use• Flow cytometry and immuno-histochemical staining to assess protein Flow cytometry and immuno-histochemical staining to assess protein

expression and phenotype expression and phenotype • Automated biochemical analyzers for metabolite analysisAutomated biochemical analyzers for metabolite analysis• Real-time polymerase chain reaction to quantitate gene expression Real-time polymerase chain reaction to quantitate gene expression

Protocol Development• Preclinical studies, sometimes referred to as preclinical development or Preclinical studies, sometimes referred to as preclinical development or

nonclinical studies, focus on obtaining safety data prior to testing in humans nonclinical studies, focus on obtaining safety data prior to testing in humans during a clinical trialduring a clinical trial

• Data from iterative and feasibility testing is also collected and analyzed Data from iterative and feasibility testing is also collected and analyzed during the pre-clinical studies during the pre-clinical studies

• The protocol contains the study plan The protocol contains the study plan

• This document allows for investigators at multiple sites to conduct the study This document allows for investigators at multiple sites to conduct the study in an identical manner, which is critical for the data to be combined and in an identical manner, which is critical for the data to be combined and analyzed togetheranalyzed together

• The protocol serves as a reference tool for study managers and The protocol serves as a reference tool for study managers and administrators, in addition to providing the investigator with a description of administrators, in addition to providing the investigator with a description of their duties and responsibilitiestheir duties and responsibilities

• In general the protocol explains the objective of the study, its design and In general the protocol explains the objective of the study, its design and methodologymethodology

• The academic investigator should work with the sponsor on protocol The academic investigator should work with the sponsor on protocol developmentdevelopment

Protocol Development• Title - name of what is being testedTitle - name of what is being tested

• Testing Facility and Sponsor Facility information - contact infoTesting Facility and Sponsor Facility information - contact info

• Study objectives – what is to be accomplishedStudy objectives – what is to be accomplished

• Regulatory compliance – following of SOP, GLPRegulatory compliance – following of SOP, GLP

• Animal welfare compliance Animal welfare compliance

• Study personnel – names, titles, trainingStudy personnel – names, titles, training

• Study schedule – when start, timelines, when completedStudy schedule – when start, timelines, when completed

• Test system information – animals usedTest system information – animals used

• Study design – a description of sequence and durationStudy design – a description of sequence and duration

• Test device information – what is being tested (test article)Test device information – what is being tested (test article)

• Technical and analytical procedures - include chain of custodyTechnical and analytical procedures - include chain of custody

• Data analysis – usually statisticalData analysis – usually statistical

• Reporting – a final report that has been audited for accuracyReporting – a final report that has been audited for accuracy

• Biosafety precautions Biosafety precautions

• Collection and retention of source data - electronic, notebookCollection and retention of source data - electronic, notebook

• Protocol amendments/deviations – changes made during progression of the studyProtocol amendments/deviations – changes made during progression of the study

Good Laboratory Practices (GLP)• Good Laboratory Practice (GLP) ensures consistency and reliability of

non-clinical laboratory and research organization results by instituting a quality system of controls

• GLP guidelines focus on the processes undertaken for non-clinical safety study planning, performance, monitoring, recording, achievement, and reporting

• GLP certification was established by regulatory agencies to garner a degree of confidence that the work submitted to them is properly conducted and adequately documented to allow for anyone skilled in the art to replicate the results

• GLP study costs are approximately 10-times the cost of conducting a non-GLP study, and are not necessary until an organization needs to obtain regulatory approval for further product development

• Since many academic laboratories do not have the infrastructure to rigorously comply with these guidelines, having an outside auditor come in and assess the level of compliance, and provide a detailed report, may be advised

Good Laboratory Practices (GLP)

A GLP study requires:

• Staff documentation, including responsibilities for all personnel involved

• An approved and valid study design

• A quality management program

• Personnel training documents

• Standard Operating Procedures (SOP)

• Study performance (including study plan and how the study will be conducted)

• Statistical analysis of study data (where applicable)

• Results reporting

• Records and reports storage

Good Laboratory Practices (GLP)

• The purpose of quality management is to make sure that mistakes are not made during the study which can negatively impact the outcome

• Quality management will focus on:

• Controls

• Record keeping

• Personnel competence for the assigned tasks

Good Laboratory Practices (GLP)

• The effectiveness of GLP guidelines is only as good as the training of the people performing the tasks

• Personnel training: • Controls• Record Keeping• Personnel competence

for the assigned tasks

Good Laboratory Practices (GLP)

1. A Standard Operating Procedure (SOP) is an approved, written procedure describing how a task or operation is to be performed

2. It ensures that operations are performed over time in as close to an identical manner as possible, and that this performance is in compliance with applicable regulations

3. The following is a list of information

essential to all SOP:• Heading• Approval or Effective Date• Version Control• Introduction• Scope• Purpose• Approval Signature• Document History

Good Laboratory Practices (GLP)

• Information headings for the remainder of the document

• The procedure itself should be described in short steps

Project Control

• The project, which is a set of interrelated tasks, should be The project, which is a set of interrelated tasks, should be ‘under control’ (maintaining the output within a desired ‘under control’ (maintaining the output within a desired range)range) by strictly adhering to the protocolby strictly adhering to the protocol

• Careful attention to detail during protocol development Careful attention to detail during protocol development should alleviate the need for amendments/deviationsshould alleviate the need for amendments/deviations

• The sponsor has project control regarding protocol The sponsor has project control regarding protocol amendments/deviationsamendments/deviations

• The academic investigator has project control regarding The academic investigator has project control regarding execution of the protocolexecution of the protocol

Intellectual Property (IP)

• Intellectual property is defined as creations of the mind for which property rights are recognized under intellectual property law

• Owners of IP are granted certain exclusive rights, thereby denying others the right to perform the same action or produce the same product in the same manner

• These exclusive rights permit the owners to benefit from the property they have created, thereby producing a financial incentive for creating and investing in IP

• A patent by itself does not grant the inventor the right to commercialize the protected technology; a patent grants the right to exclude others from commercializing it

Intellectual Property (IP)

• Continuing to secure additional IP, as well as leverage existing IP, are critical to a company’s success

• Ultimately, IP needs to be translated into a revenue-generating product for a company to enjoy some degree of financial stability

• A discussion regarding ownership of IP needs to take place well in advance of any work performed

Publication Rights

• A clear description of A clear description of publication policy (i.e.: who publication policy (i.e.: who owns the data, who needs to owns the data, who needs to be consulted as to if or when be consulted as to if or when the data can be published, who the data can be published, who is responsible for publications) is responsible for publications) should be included in the should be included in the ProtocolProtocol

• This description is often This description is often provided by the sponsorprovided by the sponsor

• Work with the sponsor to Work with the sponsor to ensure that this policy is ensure that this policy is compatible with the academic compatible with the academic laboratory/institution policylaboratory/institution policy

Assets appealing to commercial sponsors

• Cell-based assays, culturing Cell-based assays, culturing techniquestechniques

• Unique Unique in vitroin vitro and and in vivoin vivo models models

• Biomaterials synthesis, Biomaterials synthesis, characterizationcharacterization

• Specialized equipmentSpecialized equipment

• A reasonably regulatory compliant A reasonably regulatory compliant operationoperation

• Commercial-friendly technology Commercial-friendly technology transfer officetransfer office

Suggested Resources

• GLP Guidelines CFR Code of Federal regulations Title 21

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58

• SOPs

http://www.biopharminternational.com/biopharm/Article/Assuring-the-Effective-Use-of-Standard-Operating-P/ArticleStandard/Article/detail/371024

• Personnel training and documentation http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegulations/MedicalDeviceQualitySystemsManual/ucm122447.htm

• Biotechnology Centershttp://www.biotech.sunysb.edu/

http://www.ncbiotech.org/

http://www.pabiotechbc.org/biotech/directory.htm

• University Technology Transfer Officehttp://www.techtransfer.umich.edu/

Summary and Closing Remarks

• Company-sponsored research agreements Company-sponsored research agreements can serve academic researchers wellcan serve academic researchers well

• Follow GLP guidelines as close as possibleFollow GLP guidelines as close as possible

• Adherence to the study protocol, timetable, Adherence to the study protocol, timetable, and final reporting are crucialand final reporting are crucial

Live Webinar on Thursday, August 16, 2012 at 2:00 PM EST. 

Registration Includes:•Access for one phone line (unlimited listeners)•Expert answers to your tough questions•Complimentary attendee package with presentation handouts•Live Q&A session (you may also e-mail your questions in advance)•No Risk! 100% satisfaction guarantee

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