Preclinical Road map for Neuroscience Drug Discovery

Preclinical Road map for Neuroscience Drug Discovery Research at Boston

Childrenrsquos Hospital Contact Robin Kleiman PhD

Director of Preclinical Research

Translational Neuroscience Center Boston Childrenrsquos Hospital

robinkleimanchildrensharvardedu

The goal of a drug discovery project team is to help clinical investigators design a successful clinical trial

This requires high confidence identification of all of the following

Correct target

Correct molecule

Correct dose

Correct duration of drug treatment

Correct subset of patients

Correct stage of disease

Correct sample size

Correct endpoints

Acceptable side effect profile

The Translational Neuroscience Center at Boston Childrenrsquos Hospital offers a range of support for researchers addressing

critical decision points required to develop a drug discovery program and enable successful therapeutic clinical trials This

roadmap provides researchers with a strategic frame work for considering key project-specific issues and where to identify

resources to help address these issues Many resources are available in public databases via collaboration with industry

partners and via the coordination of services through the Translational Neuroscience Center at Boston Childrenrsquos Hospital

All feedback and suggestions are welcome

Other factors to consider

Phenotypic ScreensDrug Repurposing

Collaborating with Industry Preserving Intellectual Property

Funding Opportunities for Drug Discovery Projects Clinical Trials

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Target identification and Validation resources

Drug targets for human disease emerge from basic research into mechanisms of disease biology Validated molecular drug

targets require that the project team address issues related to Rationale Druggability Mechanism and Safety The

Commercial viability of the approach may also be critical for recruiting industry partners at key junctures to support

development

The Molecular Target is the protein that will bind directly to the proposed drug A validated target has

Rationale

A human genetic or pharmacological link to a selected disease population

bull Modulation of the target has been shown to produce therapeutic benefit in an in vivo animal model of the disease

population or of the relevant circuit dysfunction using a directly translatable and quantifiable endpoint

Druggability

bull A tool compound exists to modulate the target or a family member

bull Biochemical and cellular assays exist to support development of SAR for on-target and off-target activities

Well-Defined Mechanism of Action

bull A clear set of laboratory objectives that specify required mode and degree of target engagement needed for

efficacy

bull Pharmacodynamic measures of target engagement are available to monitor activity in animals and people

bull Disease induced changes in target expression or distribution have been examined

bull Common human SNPs in target documented and functional consequences considered

Safety Risk Assessment

bull Known pharmacological risks associated with target mechanism are documented

bull The tissue distribution of the target is understood in preclinical species humans and patients

bull The most likely off-target activities associated with closest sequence homology are identified and considered for

safety risks

Commercial Potential

bull Competitive differentiation strategy suggests improvement over standard of care

bull Viable intellectual property and product development plan

Download a short guide to Acronyms and Terminology associated with Drug Discovery

ACRONYMSampTERMpdf

Download an Introductory Slide Deck on the Drug Discovery Process for Neuroscience

roadmapoverviewkleimanpdf

Download an Introductory slide deck on the Role of the Biology Team in a drug discovery program

drug discovery biologykleimanpdf

Below are listed databases and other resources that can help address questions about rationale distribution of target or its

relationship to other disease genes

RNA expression data sets

GEO- Gene Expression Omnibus data base of all published RNA expression data sets

httpwwwncbinlmnihgovgeo

Allen Brain Atlas- database of brain RNA expression data httpwwwbrain-maporg

Brain Span database-Brain RNA expression data including transcriptome and ISH for human brain

httpwwwbrainspanorg

Human genome resources at NCBI

httpwwwncbinlmnihgovgenomeguidehuman

OMIM- human genes and inherited disorders maintained by Johnrsquos Hopkins

Gene Database- database of genes and associated information

dbSNP- a database of SNP and other nucleotide variations

dbGaP- database of Genotypes and Phenotypes

NextBio Free Harvard enterprise account

Mine transcriptional profiling studies for changes in your target

Search connectivity map for compounds that modulate your target

Correlate human data to animal models and cell lines

Compare disease profiles across cohorts and stages of disease

wwwnextbiocom

iHOP--information Hyperlinked Over Proteins

A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP

Ingenuity Pathway Analysis

Available from research computing Find disease related literature for your target

httpwwwingenuitycomproductsipa

TISSUES database of Expression of targets (RNA and Protein)

TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated

literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common

protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate

comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human

body to provide a convenient overview

httptissuesjensenlaborgSearch

Refrence Literature related to target identification and validation

Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015

11(6)368-372 httpwwwncbinlmnihgovpubmed15718163

Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of

novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl

1S8 httpwwwncbinlmnihgovpubmed25077696

Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug

discovery 2013 12(8)581-594 httpwwwncbinlmnihgovpubmed23868113

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Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance

with identification of academic and industry partners for collaborative SAR campaigns

Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening

funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria

for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency

(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing

paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily

treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of

the screening funnel required to identify the molecule

The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds

good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the

compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined

by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to

progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and

target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must

be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require

pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing

Link to sample Screening Funnels

httpswwwnimhnihgovresearchprioritiestherapeutics

The types of information needed to Characterize a Lead Compound are summarized here

httpswwwnimhnihgovresearch-prioritiestherapeuticsCompound_Report_Card_143596pdf

Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr

Johnny Bennett Merck

Childrens MedChem 29Jul2015pdf

Resources for assay development

The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196

This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many

different modes of assay development and optimization as well as troubleshooting guides Do not run a screen

without consulting the manual first

The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance

consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett

LeeBarrettchildrensharvardedu

Website httpschildrenshospitalcorefacilitiesorgservice_centershow_external3142bch-assay-development-

screening-facility

The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput

screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu

caroline_shamuhmsharvardedu

Website httpiccbmedharvardedu

Databases and references with information about activity and properties of small molecule compounds

PubChem provides information on the biological activities of small molecules PubChem is organized as three linked

databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and

PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on

biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to

PubChems bioassay database present the results of biological screening Links to depositor web sites provide further

information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix

Service Structure Clustering and Deposition Gateway are also available Home page is here

httpspubchemncbinlmnihgov

httpspubchemncbinlmnihgovsearch

DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug

(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and

pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161

FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300

non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each

DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and

the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca

Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design

Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology

This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and

complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from

protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo

High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by

virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are

detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the

biology community the industrial chemistry research community has joined a pre-competitive effort to provide

characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-

family

ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH

with a current and comprehensive database of commercially accessible drug discovery screening compounds to be

made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound

sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a

few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples

of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp

Additional References related to biological activity of compounds

Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature

chemical biology 2009 5(7)436-440

Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update

Nucleic acids research 2014 42(Database issue)D1075-1082

Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of

the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266

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Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references

Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species

requires that you know the potency of the molecule at the desired drug target and the dose of compound required to

achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage

the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the

databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the

concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature

reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here

Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs

Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121

If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood

brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis

Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery

courtesy of Dr Chris Shaffer Pfizer

150805DMPKTutorial(CLSBCHCourse)pdf

Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis

Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood

urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future

clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric

formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications

and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in

the identification of resources for pharmacodynamic assay development and contract research organizations able to

provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more

information LuisPereirachildrensharvardedu

article on importance of understanding drug exposure in preclinical drug studies here

References on Pharmacokinetics and Brain Penetration of Small Molecules

Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of

medicinal chemistry 2013 56(1)2-12

Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving

new concept Chemistry amp biodiversity 2009 6(11)2030-2049

Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature

reviews Drug discovery 2010 9(12)929-939

Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico

ADME models Bioinformatics 2008 24(19)2270-2271

Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40

shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097

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Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core

To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation

and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since

most drugs developed for humans are optimized for human metabolism parameters many compounds developed for

humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical

administration (see tutorial under Correct Dose)

Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design

The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and

training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also

available through the Neurodevelopmental Behavioral Core

Contact is Dr Nick Andrews NickAndrewschildrensharvardedu

httpcoreiddrcorgneurodevelopmental-behavioralpage_id=356

Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core

or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu

The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi

RoccoAnzaldichildrensharvardedu

idspharmacy-dlchildrensharvardedu

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Stratification Biomarker development and resources patient sample repositories requests for collection of new types of

patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases

Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same

disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions

Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous

populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from

patient samples a structural or a functional feature of a human imaging technology or a functional measure of an

electrophysiological readout

The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors

experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-

innovationresearchcenterstranslational-neuroscience-center

Other avenues for biomarker development include

Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG

signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors

CharlesNelsonchildrensharvardedu

JurriaanPeterschildrensharvardedu

MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits

in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu

Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-

based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors

LouisKunkelchildrensharvardedu

ChristopherWalshchildrensharvardedu

The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit

specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support

differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman

RobinKleimanchildrensharvardedu

Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on

assay development for use in clinical trials Translab website with contact information can be viewed here

httpwwwtranslabbostonorg

TransLab Flyer 2 2015pdf

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Patient sample repositoryBiobank Patient registry

Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and

response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding

which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from

patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of

disease

To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease

search databases referenced in the Correct Target section of this document

The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The

Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The

biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and

requested through the Translational Neuroscience Center

The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston

Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional

perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research

and discovery

The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor

repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to

these resources

StephanieBrewsterchildrensharvardedu

KiraDieschildrensharvardedu

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Statistical support clinical trialsgov

Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into

account the variability of the endpoint being measured Statistical support for preclinical studies is available on a

department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made

through the CRC website

httpredcap-qiredcap_edcsurveyss=Rma5u83qKC

Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more

information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu

Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov

database All studies in the clinical trials data base are required to describe the study design the endpoints under

evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can

be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will

be needed to support sample size power calculations httpsclinicaltrialsgov

Resources for preclinical study design

httpwwwnindsnihgovfundingtransparency_in_reporting_guidancepdf

httpinformahealthcarecomdoipdf10310917482960903545334

httpwwwncbinlmnihgovpubmed23874156

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Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols

Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search

of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be

competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical

species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest

trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for

preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG

visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based

behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic

Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health

disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of

translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical

Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical

endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC

The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators

on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers

human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors

DeborahWaberchildrensharvardedu

Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by

the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie

Brewster Co-Directors

Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml

Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework

Biological psychiatry 2014 76(5)350-353 httpwwwncbinlmnihgovpubmed25103538

Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126

httpwwwncbinlmnihgovpmcarticlesPMC3653747

Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)

toward a new classification framework for research on mental disorders The American journal of psychiatry 2010

Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal

of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194

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Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for

Investigational New Drug (IND) applications

Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in

order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be

aware of differences in distribution of the target and related family members in preclinical species Many of the target

expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used

to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance

compounds

Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the

presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts

can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help

deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q

Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg

Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a

qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies

needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are

qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer

Brady boston childrens hosp talk aug2015 IND toxpdf

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Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research

projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access

to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources

antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics

modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range

of models of interacting with industry in a range of different capacities Some frequently asked questions about types of

relationships and the responsibilities associated with those interactions can be found in the following document

Download Frequently Asked Questions about working with Industry

TIDO_Company_relationships_FAQpdf

httpwwwchildrensinnovationsorgdocsTIDO_Company_relationships_FAQpdf

main menu

Laboratory notebook best practices TIDO office

Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing

hypotheses into commercial products Industry partners capable of developing these potential products need to be able

to license the intellectual property required to sell the product in order to justify investment in building programs around new

ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future

commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their

work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO

before any public disclosures of new research Similarly the following documentation provides guidance for documenting

your work according to standards that will support patent applications

Download the compliance manual for BCH for Intellectual property policy

cm_021_intellectual_propertydocx

Download a summary of laboratory notebook Dorsquos and Donrsquot

Dosdontsnotebookspdf

Link to TIDO Technology Innovation and Development Office

httpwwwchildrensinnovationsorgPagesPatentsAndLicensingPatentsAndLicensingaspx

main menu

A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human

biology It can be used to identify molecular targets for target validation studies through the use of well-annotated

bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify

novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely

on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system

The strengths of this approach

Use of human systems can improve translatability

Identified compounds may empirically balance therapeutic activity at multiple required targets

Well-suited to drug repurposing

Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs

Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)

Drawbacks to this approach

Assays are slow low throughput and more expensive as compared to cell-free assays

Cell-based assays may not predict circuit level or brain phenotypes

Furthermore as a primary screening approach

Precludes leveraging strengths in uHTS SBDD and parallel design

Every molecule must be de-risked independently thus safety can be very hard to predict

Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)

Details on resources and funding opportunities can be found here httpsncatsnihgovntu

Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are

designed to cover the druggable genome with small molecule compounds from their proprietary collections Each

company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO

regarding terms and conditions associated with individual companies

ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that

include bioactive or FDA approved molecules available for screening

ICCB libraries httpiccbmedharvardedulibrariescompound-libraries

Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu

References related to phenotypic screens and Drug Repurposing

Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T

and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15

(2015)

Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and

definitions in literature Drug Discov Today (2015)

Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-

519 (July 2011) | doi101038nrd3480

main menu

TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC

Glossary of Terms

Glossary-of-Clinical-Trials-Termspdf

Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the

Translational Neuroscience Center providing coordination among studies communications resource development and

implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development

and launching of new studies The directors are available to guide TNC researchers in designing human studies including

the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and

Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study

coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and

Stephanie Brewster MS CGC

Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources

in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices

The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and

highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH

community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center

Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design

initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for

pediatric conditions httpweb2tchharvardeductsu

Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators

and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a

research study and provides embedded links to institutional resources tools and documents

Clinical Research Mappdf

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Office of Sponsored Programs Research Administration TIDO

Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of

funding options exist on OSP and Research Administration web sites

Some good options for finding relevant requests for proposals

Translational Research Program annual call for proposals

httpwwwchildrenshospitalorgresearch-and-innovationresearchtranslational-research-programpilot-grants

Technology Development Fund

httpwwwchildrensinnovationsorgPagesTechnologyDevelopmentFundTechnologyDevelopmentFundaspx

Harvard Catalyst httpscatalystharvardeduservicespilotfunding

Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash

Broad Institute committee Additional submission dates are expected for 2016

BCH_Broad collaborative grant 852015docx

Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available

Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through

TNC e-mail lists

ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational

research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and

universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to

treatment prevention and early detection are also supported

httpswwwalzdiscoveryorgresearch-and-grantsapply-for-funding-Academic

Childrens Tumor Foundations A comprehensive approach to improving the lives of individuals and families affected by

neurofibromatosis (NF) Drug Discovery award applications can be found here httpwwwctforgCTF-Awards-Grants-

and-ContractsDrug-Discovery-Initiative

Wellcome Trust Seeding Drug Discovery initiative Funding to facilitate early-stage small-molecule drug discovery The

awards help applicants with a potential drug target or new chemistry embark on a program of compound discovery

andor take later stage projects towards clinical trials httpwwwwellcomeacukFundingInnovationsAwardsSeeding-

Drug-Discoveryindexhtm

Cure SMA Drug discovery proposals Their pre-clinical drug discovery program invests funding innovate and promising

projects that will lead directly to creating viable drug for treating SMA Each year their Translational Advisory Council issues

a request for proposals Check website for more information about dates

httpwwwcuresmaorgresearchfor-researchersfunding-opportunitiesdrug-discovery-funding-opportunities

TREAT ALS Drug Discovery Contract Open Submission The ALS Associationrsquos Translational Research Advancing Therapies for

ALS (TREAT ALStrade) program funds research from early target identification to preclinical research and early pilot clinical trials

As part of the program the Association is requesting letters of intent for its drug development contract program milestone

driven research to develop new treatments for ALS The program complements the Department of Defense ALS research

program and the translational programs at the National Institutes of Health

httpwwwalsaorgnewsarchivetreat-alshtmlreferrer=httpswwwgooglecom

Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense

Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis

research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency

Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program

(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated

Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)

httpcdmrparmymilpubspress201515alsrppreannshtml

Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the

pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological

surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally

altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care

Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is

open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe

therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28

NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and

seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I

clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories

as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry

pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had

years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug

development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can

readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the

network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators

(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their

institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants

who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug

candidates developed through the network and eventually pursue licensing and commercialization partnerships

httpneuroscienceblueprintnihgovbpdrugs

NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to

develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a

stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the

administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement

evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers

NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml

Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -

See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf

NCATS many grant options see overview here httpwwwncatsnihgovprograms

Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical

resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not

receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who

conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and

toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available

httpwwwncatsnihgovbridgsworksolicitation

NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed

to develop partnerships between pharmaceutical companies and the biomedical research community to advance

therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry

assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients

httpwwwncatsnihgovntu

Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project

rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest

include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases

cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH

members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common

goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both

Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January

May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx

Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-

Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized

through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested

Unsolicited proposals may also be considered from time to time

ACRONYMS

HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total

uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers

HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints

SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical

properties

PK- Pharmacokinetic measure of drug levels in a body compartment

PD- Pharmacodynamic a measure of functional activity of a drug

PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system

DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )

DMPK- Drug Metabolism and PharmacoKinetics

ADME- Absorption Distribution Metabolism amp Excretion

PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND

and NDA

POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response

POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved

PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy

FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1

FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and

contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development

IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people

NME- New Molecular Entity- a new FDA approved drug

NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug

CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved

in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings

SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities

MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns

TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)

Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070

Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in

the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)

Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like

molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a

particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along

with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be

modulated to correct a phenotype (Poly-pharmacology)

Terms that relate to programs

Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip

Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc

Therapeutic Modality- small molecule biologic RNAi stem cell etc

Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives

Terms that relate to molecules

Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity

Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10

Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)

Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo

Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay

Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series

Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore

intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety

Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease

intervention hypothesis in humans

A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks

1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed

2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed

An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)

3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space

4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries

5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed

6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed

Fish amp Richardson pc

Dorsquos and Don rsquo ts forKeeping Lab Notebooks

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary

8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope

9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook

10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)

11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship

12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided

13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him

14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years

By J Peter Fasse

Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom

P ER SP EC T I V E

PHARMACOK INET I CS

Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2

The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design

on January 6 2016httpstm

sciencemagorg

nloaded from

Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true

Preclinical pharmacological experimentsthat do not measure drug concentrations in

1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)

the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)

Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These

wwwScienceTranslationalMedicineo

issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders

DOCUMENTING DOSING STRATEGIES

To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)

The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding

rg 6 January 2016 Vol 8 Issue 320 320ps1 1

P ER SP EC T I V E

sciencemagorg

nloaded from

to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound

and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis

The lack of pharmacokinetic considera-tion does not imply that every study used an

inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate

DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)

The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce

Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior

Rationale for studyrsquos drug-dose selection

Therapeutic

studies

Number of papers from the100 published studies

analyzed

bull No exposure or rationale for dose selection provided

bull Rodent dose extrapolated from human studies

bull Doses are similar to what was used previously toproduce a biological effect

bull Literature reports cited for multiple functionaleffects of drug at selected dose

bull Brain penetration evaluated but exposure notmeasured

bull Literature report of mismatched drug exposure

bull Observation of a biological effect at a single dosein current study

bull Observation of dose-responsive biological effectin current study

bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study

bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy

bull Plasma drug concentrations measured

bull Brain pharmacodynamic effect of drug observed

bull Brain drug concentrations measured (totalconcentration)

bull Unbound brain drug concentrations measured

bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed

P ER SP EC T I V E

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nloaded from

risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)

A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile

A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin

required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class

The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems

FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant

data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)

Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis

Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database

Literature reports that evaluate studydrugs should include

Compound-specific data that shouldbe included in a rodent

pharmacokinetic database

bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy

bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)

bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study

Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration

bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy

bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure

bull Expected or measured potency of the studydrug against the hypothesized activity in vitro

Expected ormeasured potency of molecule at knownbiological targets

P ER SP EC T I V E

sciencemagorg

nloaded from

A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials

Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups

and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs

Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation

SUPPLEMENTARY MATERIALS

wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains

REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-

tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)

2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)

3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)

4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)

5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)

6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)

7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)

8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)

9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)

10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)

11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)

12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)

13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)

14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)

15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)

16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)

17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)

18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)

19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)

Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data

Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices

Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists

bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools

Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure

Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion

bull Targeted data collection for compounds already in the public domain

P ER SP EC T I V E

20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)

21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)

22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)

23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)

24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)

25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)

26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)

27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)

28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)

29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)

30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)

31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)

32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)

101126scitranslmedaac9888

Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)

sciencemagorg

ownloaded from

101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine

Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research

Editors Summary

This information is current as of January 6 2016 The following resources related to this article are available online at httpstmsciencemagorg

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Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants

Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists

Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics

middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute

middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital

middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects

Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute

Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics

Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration

Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016

Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)

BOSTON CHILDRENrsquoS HOSPITAL-BROAD INSTITUTE

COLLABORATION GRANT PROPOSAL

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

BCH PRINCIPAL INVESTIGATOR

_________________________________________________________________________________________________________________

BROAD COLLABORATORS

__________________________________________________________________________________________________________________

TOTAL YEAR 1 COST (DIRECT ONLY MAXIMUM $60000)

__________________________________________________________________________________________________________________

1) SUMMARY (CONCISE SUMMARY OF PROJECT AND ITS GOALS)

__________________________________________________________________________________________________________________

2) RATIONALE FOR FUNDING (LESS THAN 12 PAGE)

(NARRATIVE DESCRIBING IMPORTANCE OF PROJECT AND APPROPRIATENESS FOR COLLABORATIVE SUPPORT)

__________________________________________________________________________________________________________________

3) PROJECT PLAN (PAGE LIMIT 2 PAGES NOT INCLUDING REFERENCES)

(OUTLINE PROJECT PLAN AND EXPECTED OUTCOMES)

__________________________________________________________________________________________________________________

4) BROAD PLATFORM USAGE (BE SURE TO DISCUSS PROPOSED USAGE IN ADVANCE WITH PLATFORM LEADERSHIP)

__________________________________________________________________________________________________________________

5) SPACE REQUIREMENTS (DESCRIBE WHERE ACTIVITIES WILL TAKE PLACE)

__________________________________________________________________________________________________________________

7) REGULATORY COMPLIANCE (DESCRIBE ANY REQUIRED IRB AND OTHER APPROVAL)

__________________________________________________________________________________________________________________

8) BUDGET JUSTIFICATION

__________________________________________________________________________________________________________________

9) BUDGET - USE THE PHS398 FORM BUDGET FORMAT AS BELOW

Boston Childrenrsquos Hospital

Broad Institute Collaboration Grants

Background

Meeting the challenges of biomedicine requires bringing together creative

scientists exceptional technological resources and world

class expertise across many

disciplines that rarely exist within a single institution This guiding principle is the basis

funding opportunity to support Boston Childrenrsquos Hospital investigators performing research

in collaboration with Broad scientists

The fundamental goal of this new award is to spark new collaborations between Boston

Childrenrsquos Hospital an

d the Broad Institute

The grants will be awarded to address a very wide

range of scientific questions but are specifically designated for projects with the following

characteristics

middot

Projects where engagement with the Broad would benefit Childrenrsquos Hosp

investigators projects that can uniquely benefit from being done at the Broad Institute

middot

Projects that create new scientific collaborations and bring together diverse scientific

backgrounds projects that spark new scientific directions or technologi

es and are not

currently being pursued at Childrenrsquos Hospital

middot

Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the

greater scientific community can benefit from in the future the purpose of these awards

to provide gap or extension funding of existing projects but to initiate new

projects

Eligibility

Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are

eligible Applicants need not be Associate Members of the Broad Institu

Broad Platforms and Scientists

Broadrsquos Platforms (Genomics Imaging Metabolite Profiling

Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative

organizations that provide scientific leadership and cutting edge technologie

s in support of

project goals Collaborations can also be established with other groups at the Broad including

the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the

Development of Therapeutics

Budgets

Grants wi

ll provide $60000 direct support for 1 year plus philanthropic overhead It

is expected that most grants will fund work performed at the Broad Institute either through

interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev

er the

work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the

collaboration

Deadline and Review process

Final proposals are due by September 1 2015 Funding

decisions are expected to be reached by October 1 201

5 Proposals will be reviewed by a joint

Childrenrsquos Hospital

Broad Institute committee Additional submission dates are expected for

Submission

Applicants are

strongly encouraged to discuss potential applications in

advance

with the office of the Chief Sc

ientific Officer at the Broad

Questions should be

directed to Alex Burgin (

aburginbroadinstituteorg

Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants

Background Meeting the challenges of biomedicine requires bringing together creative

scientists exceptional technological resources and world-class expertise across many

disciplines that rarely exist within a single institution This guiding principle is the basis for a

Goals The fundamental goal of this new award is to spark new collaborations between Boston

Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide

characteristics

Projects where engagement with the Broad would benefit Childrenrsquos Hospital

backgrounds projects that spark new scientific directions or technologies and are not

is not to provide gap or extension funding of existing projects but to initiate new

projects

Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are

eligible Applicants need not be Associate Members of the Broad Institute

Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling

organizations that provide scientific leadership and cutting edge technologies in support of

Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It

interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the

collaboration

Deadline and Review process Final proposals are due by September 1 2015 Funding

decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint

Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for

Submission Applicants are strongly encouraged to discuss potential applications in

advance with the office of the Chief Scientific Officer at the Broad Questions should be

directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)

Clinical Trials Glossary

ADME an acronym for absorption distribution metabolism and elimination ADME

studies determine how a drug is absorbed by the body the chemical changes that it may

undergo and how it is eliminated from the body

Adverse event (AE) a bothersome event that occurs in a study participant AEs may be

related to the treatment being tested or may be due another cause (eg another treatment

another medical condition an accident or a surgery)

Arm a specific type of treatment to which a group of clinical trial participants is

assigned Some clinical trials have one arm and some have two arms while others have

three or more arms For example a clinical trial comparing two different doses of an

investigational drug versus a placebo would have three arms participants receiving a

higher dose of the investigational drug participants receiving a lower dose of the

investigational drug and participants receiving the placebo

Baseline a point in time at the beginning of a clinical trial before the study participants

receive any treatment At the baseline participants usually have certain types of tests

During and after treatment the same tests may be performed and the results compared

with the baseline results to see if the drug has caused changes

Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a

treatment or a lack of balance in selection of patients for a study ndash that reduces the

likelihood that the study results are true Methods such as blinding and randomization

are used to limit the potential for bias

Bioavailability the portion of the dose of a drug that reaches the bloodstream For

example if the drug is administered intravenously its bioavailability is 100 percent

however if the drug is administered in any other way such as orally topically or

through intramuscular injection its bioavailability will decrease due to incomplete

absorption

Bioequivalence study a test performed to compare the portion of a drug in the

bloodstream when administered in different dosage forms

Biologic product any substance that can be used in prevention treatment or cure of

disease Some examples include vaccines blood virus toxin antitoxin and therapeutic

Biopsy the removal of cells or tissue from a patient for examination which is usually

done under a microscope A tissue sample might be taken for genetic studies Sometimes

there is a difference between the blood genotype and the skin or other tissue genotype

This term can also refer to the tissue sample that has been obtained by such a procedure

Blinding a process used to prevent the participants the researchers or both from

knowing what specific treatment is being given to participants in a clinical trial The

process of blinding helps to reduce bias because study participants and researchers are

less likely to be unconsciously influenced by the knowledge of what the study participant

is actually receiving If only the participants are blinded the study is called a single-

blind study If both participants and researchers are blinded the study is called a double-

blind study

Carcinogenicity studies long-term studies conducted in animal models to determine a

drugrsquos likelihood of causing cancer

Clinical efficacy a compoundrsquos ability to produce the desired effect

Clinical pharmacology a science that studies properties of drugs in relation to their

therapeutic value in humans

Clinical study or Clinical trial a medical experiment in human beings that helps to

determine how a disease drug or medical device affects study participants Clinical

studies are necessary to answer specific questions about how to better diagnose prevent

or treat a disease or condition

Cohort a group of study participants who have certain characteristics in common such

as female sex a defined age range or particular severity of disease Dividing study

participants into cohorts is often done as part of the analyses of study data

Contraindication a factor that makes the use of a particular drug inadvisable For

example a person who has had an allergic reaction to penicillin in the past is considered

to have a contraindication to using penicillin in the future

Control group a group of participants not receiving the investigational drug but instead

receiving a standard treatment for their disease or receiving a placebo The results

observed in the group of patients receiving the investigational drug are compared with the

results observed in the control group

Crossover study a study design with two or more arms where participants receive one

treatment for a period of time and then switch over to a second treatment for a period of

time Such a study design allows the effects of the two treatments to be compared in the

same patient

Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)

A committee of experts that periodically reviews the accumulating data from an ongoing

multicenter clinical trial Members of a DMCDSMB must be independent ie they

cannot be participating as investigators in the clinical trial Based on their review the

DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to

continue with the study or whether the data suggest that the study should be modified or

stopped A DMCDSMB may recommend that a trial be stopped if there are safety

concerns or if the trial objectives have been achieved

Dose-ranging study a clinical trial in which two or more doses of an investigational

drug are tested to determine which dose is likely to offer the best combination of safety

and efficacy in later clinical trials or in medical care

Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition

Eligibility a determination made during the screening period for a clinical study of

whether a personrsquos participation in the trial is likely to be safe and can contribute data

that will help achieve the study goals

Endpoint occurrence of a disease symptom sign or test result that constitutes one of the

target outcomes of a clinical trial

Inclusionexclusion criteria the factors defined in the protocol of a study that determine

whether a personrsquos participation in a clinical trial is likely to be safe and can contribute

data that will help achieve the study goals Study candidates undergo evaluation during

the study screening period to determine if they meet all of the inclusion criteria and do

not meet any of the exclusion criteria as defined in the protocol These criteria usually

consider such factors as age sex type of disease stage of disease previous treatment

history and other medical conditions in determining eligibility for the study

Informed consent (assent) a process by which medical researchers provide necessary

information to a person about a clinical study and the person voluntarily confirms his or

her willingness to participate in the study Children who are considered old enough to

have a basic understanding of the study may need to provide assent to be involved in the

study a parent or legal guardian must also give informed consent for such a child to

participate

Informed consent (assent) form a document that describes a clinical study to the

participants (or their parentsguardians) The informed consent (assent) form includes

information about the goals of the study the study design and duration the types of tests

to be performed the potential risks and inconveniences the potential benefits the

possible costs or payments associated with study participation the available alternative

therapies the rights and responsibilities of the participant and the people to contact if the

participant has questions The informed consent (assent) form must be reviewed and

signed before the participant has any study tests or treatment including the tests

performed during the screening period at the beginning of the study Participants are

given a copy of the informed consent (assent) form to take home

Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board

of physicians statisticians researchers community advocates and others who are

responsible for ensuring the protection of the rights safety and well-being of participants

in a clinical trial at a study center This board is called an IRB in the United States and is

often called an IEC in other countries IRBIECs review and approve important study

documents (eg protocols informed consent forms study advertisements and patient

brochures) before the start of the study and periodically review the progress of the study

while it is ongoing

Investigational Drug a drug that is being tested as a potential treatment for a disease or

condition but has not yet been proven safe and effective for that use

Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results

In vitro testing testing conducted in test tubes or other artificial environments

In vivo testing testing conducted in living animals or humans

Longitudinal study a clinical study that involves observations of the same items over

long periods often many decades Because longitudinal studies track the same people

they are often used to study trends across the life span to uncover predictors of certain

diseases or to track the effects of a particular treatment on a patientrsquos condition over

Multicenter study a study conducted at more than one location Multicenter clinical

studies are generally performed when each individual clinical trial site does not have

enough study candidates to complete a large trial

Natural history study a study of the natural development of a disease or condition over

a period of time Natural history studies are usually longitudinal studies

New Drug Application (NDA) the registration document through which a

pharmaceutical company formally proposes that the FDA approve a new drug for

manufacturing and sale The application includes detailed reports of pharmacology

toxicology manufacturing and chemistry as well as data from clinical trials

Open-label study a study in which the participants and the investigators know which

treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo

Orphan disease a disease or condition that affects a relatively small number of people

In the US this defined as fewer than 200000 people In Europe this is defined as fewer

than five in 110000 people

Orphan drug a drug intended to treat an orphan disease

Participant or subject a patient or healthy volunteer who participates in a clinical trial

Phase 1 the initial phase of testing of an investigational drug in humans Usually a

Phase 1 clinical study is conducted in a small number of healthy volunteers or patients

with a disease for which the drug may be useful Generally the study is designed to

determine the side effects of the drug and its pharmacokinetics Some information

regarding drug efficacy may be collected if patients with a disease participate A phase

frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided

into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is

performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is

performed in patients with a disease

Phase 2 the intermediate phase of testing of an investigational drug in humans Usually

a Phase 2 clinical study conducted in patients with a disease for which the drug may be

useful Generally the study is designed to evaluate dosing to obtain preliminary data on

the effectiveness of the drug and to acquire more safety information Phase 2 sometimes

is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter

in duration and evaluate different drug doses to see how they affect certain tests that can

indicate whether the drug is working as expected Phase 2b studies typically enroll more

patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed

Phase 3 the final phase of testing an investigational drug in humans before regulatory

approval Phase 3 studies are usually conducted in a large population of patients and are

generally designed to confirm the effectiveness of the drug and to evaluate the overall

risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with

a standard treatment for the disease or a placebo

Phase 4 testing of a drug in humans after it has already been approved by regulatory

authorities and can be used in medical practice Phase 4 studies may be conducted to

compare the drug to a similar type of drug to explore whether it may help patients with

other diseases to further study the long-term safety of the drug or for other reasons

Pivotal study a study that is designed to generate the data required by regulatory

authorities to decide whether to approve an investigational drug A pivotal study is

usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a

placebo as a control Sometimes a pivotal study is described as a registration-directed

Placebo an inactive version of an investigational drug A placebo has a similar

appearance to the investigational drug but is expected to have no therapeutic value A

placebo is used as a comparison treatment to reduce bias in randomized studies

Preapproval access program an umbrella term for programs that allow seriously ill

patients to receive an investigational drug when they are unable to participate in clinical

trials and there is no alternative treatment This is sometimes referred to as

compassionate use Types of pre-approval access programs include expanded access

parallel-track named patient program single-patient exemption and treatment IND The

timing for starting an expanded access program usually depends upon what is known

about the risk-benefit of the drug and whether the drug can be provided in a manner that

is fair to patients with the disease

Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug

undergoes preclinical testing before being tested in humans to make sure that it shows

evidence of desired effects and is sufficiently safe for study in people Preclinical testing

sometimes also helps to determine the doses of the drug that should be evaluated in

humans Preclinical testing is sometimes called nonclinical testing

Protocol a document describing what types of people may participate in a clinical study

and the objectives treatments measurements statistical methods timing and

organization of a clinical trial The protocol must be prepared in advance of the study

and must be reviewed and approved by review committees and regulatory authorities

before the study is started Investigators must follow the protocol to carry out the study

Randomization assignment of participants to treatment arms based on chance This is

usually done by a computer program in a way that does not allow either the participants

or the investigators to choose who is assigned to which arm Randomization is used to

reduce bias in clinical trials

Risk-benefit ratio the balance of the risk of side effects expected with use of a drug

versus the potential for benefit with the use of that drug A drug with a good risk-benefit

ratio has few side effects and is very effective

Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient

hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth

defect or results in death

Side effect any effect of a drug other than the desired effect Side effects are often

unwanted and may be bothersome Other names for a bothersome side effect are adverse

drug reaction (ADR) or drug toxicity

Screening period a period at the beginning of a clinical trial when candidates for the

study are evaluated to determine if their participation is likely to be safe and can

contribute data that will help achieve the study goals

Significant or statistically significant an outcome in a clinical trial is likely to result

from a real difference (eg due to an effect of a treatment) and is unlikely to be due to

chance alone The level of statistical significance is often expressed in terms of a p-

value which indicates the probability that a difference is not due to chance alone

Usually a p-value smaller 005 is considered statistically significant

Sponsor the organization responsible for financing and coordinating a clinical trial

Most often this is a pharmaceutical or biotechnology company

Standard treatment a treatment currently in wide use often approved by regulatory

agencies and generally considered effective in the treatment of a specific disease or

condition

Toxicity a side effect produced by a drug that is bothersome to the person taking the

Toxicology the study of the adverse effects of chemicals conducted in animal models to

predict potential adverse effects in humans Some studies are conducted during clinical

development to evaluate dosing regimens

Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink

CLINICAL RESEARCH MAP

ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents

An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study

For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study

This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol

This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams

ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources

Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing

Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery

Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology

Laura Feloney BA Lab Technician

ContentsOverview Four stages 3

1st Stage Protocol development 4

1st Stage Protocol development contrsquod 5

2nd Stage Implementation planning 6

3rd stage Study launch7

4th stage Statistical analysis reporting and dissemination 8

Discarded specimens Additional steps 9

Chart review Steps if you are completing a chart review 10

Appendix A Resources for researchers 11

Overview Four stages

Protocol development

Implementation planning

Study launch

Statistical analysis reporting and dissemination

1st Stage Protocol development

Explore resources

Harvard Catalyst

Complete training

CITI training

Consult research pharmacistResearch Pharmacy

Rocco Anzaldi

Consult statistician

Draft a protocol

Protocol guidelines

Study personnel

FDA Guidance for Investigators

Consult Clinical Research Center

Bio Bank

Start IRB application

TransLab

Consider applying for grants

securing funding

Office of Sponsored Programs

If INDIDE application to FDA

Does my study need an INDIDE

Regulatory resources

Arrange a consultation with

ConsultationTasks for investigators and study teams

Respond to IRB questionsrequests

for clarification

1st Stage Protocol development contrsquod

Departmental Scientific Review

Organize DSMB design DSMP

DSMPDSMB

Templates for Research Study

Documents and Tools

Study Templates and Tools

Investigators who sponsor an FDA regulated trial

ClinicalTrialsgov

Create regulatory binder

Regulatory Binder Template

Submit the grant application to OSP

Consult Office Intellectual Property

Technology and Innovation

Development Office

IRB approval

Consider blood volume for research

Research blood volume policy

Confidentiality plan

Confidentiality guidelines

Develop Case Report Forms

(CRFs)

CRF guidelines

Establish electronic shared

folder or study binder for study

documents

Set date for trial launch

Develop fast fact sheet for bedside staff

Consult programmer re database

Research study resource manual

for the clinical unit

Confirm study drug

in pharmacy

Rocco Anzaldi

Clarify system for screening

and enrolling patients

Recruitment guideline

Updated protocol to

nurse manager

Consult MDsNPs on unitclinic

2nd Stage Implementation planning

Tasks for investigators and study teams

Study logistics Documentation logistics

Data storage

Create study orderset

Create Manual of Operations

MOO Guide

Study implementation

meeting

Develop study logstools

Finalize tracking sheet

Research Administration

Fernando Valles

3 Document informed consent

Informed Consent

Consent library

Schedule weekly study team meeting

Communicate to department faculty

and multidisciplinary

team announcing trial launch

Steps before trial launch

3rd stage Study launch

Patient flow

1 Seek permission

to approach potential subjects

2 Screenenroll

patients

5 Send Study

Tracking Sheet (STS)

6 Collection of

patient data and assessing for

adverse events

7 Study

documents and data handling

4 Datetime study tests

Create a checklist outlining study action items for each subject

Annual IRB Report

Annual Progress ReportStaff Report

raquo Maintain Interest of Staff

raquo Important to See Study Progress

Write Abstract

Dissemination of Research Results

raquo Conference raquo Internal Presentation for Colleagues

raquo Publication

Plan DSMB MeetingInterim

Analysis

4th stage Statistical analysis reporting and dissemination

Data Entry

When Enrollment Complete Data

Cleaning

Monitor Subjects to Identify

Adverse Events (CCI sponsor

Report Adverse Events

Update MOO Based on Experience

with First Several Patients Enrolled

Weekly Study Team Meeting

Report study findings to

subjects and stakeholders

Data management Trial management

Reporting Dissemination

Regular Review of Data

to Identify Deviations

and Workflow Improvements

Consult Statistician When Approaching Target Enrollment

Discarded specimens Additional steps

Send IRB Approval to lab manager

Maureen Samson

Educate staff in areasunits about sample collection

Locate the discarded samples

Locate the accession number in PowerChart

Retrieve specimen

Mark Kellogg

Follow Shipping Rules and Procedures

IATAShipping with dry ice instructions

Communicate with laboratory staff

Contact Dr Mark Kellogg to discuss specimen retrieval

Consult with Biorepository

Biorepository

Chart review Steps if you are completing a chart review

Databaserecord review guidelines

CRC Request

Respond to IRB questions

requests for clarification

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

Prepare IRB Application

Information about the CCI

IRB Application

Develop Case Report Forms (CRFs)

CRF Guidelines

IRB Review

Clinical Research Center (CRC) x84720

Committee on Clinical Investigation (CCI IRB) x57052

Research Pharmacist x52014

Clinical and Translational Science Unit (CTSU) x57541

Education and Quality Improvement Program (EQUIP) x57052

Clinical Trials Office Central Budgeting x4-2714

Office of Sponsored Programs x4-2723

Technology and Innovation Development Office 617-919-3079

Research Finance x8-3517

Harvard Catalyst 617-432-7810

Regulatory Affairs x4-2777

Appendix A Resources for researchers

RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1








Chart reviewSteps if you are completing a chart review











RES_4446_ClinicalResearchMap-PAGE 5pdf










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Button 91

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IRB review

Button 102


Button 136

Consult clinical research center

INDIDE 1

Explore resources

Button 1016

Bio Bank p

4


Consult research pharmacist

Study personnel

Complete training

Consider grantsfunding

Draft a Protocal 2

Arrange a consutlations with CRIT

Next Page 1

Previous Page 1

TransLab

Start IRB application 3

Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system

Research study resrouce manual

Develop case report forms

MOO


Button 44

Study implementation meeting


Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71

Screenenroll patients

Document informed consent

Datetime tests

Send study tracking sheets

Collection patient data

Button 77

Dissemination

Button 87

Button 124

Button 125

Communicate with lab staff

Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository

Locate assession number

Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66


Templates for research stufy

Clinical Trials Business Office

Blood volume 2


Investigators who sponsor

clinicaltrials

gov

BPN Project

Drug Discovery amp Development Testing Funnel

Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4

Example Drug Discovery amp Development Testing Funnel

Cytotoxicity

Grant

Project


TIER 1A ndash Primary Screen

Chemical purity and identity of active compounds

Primary bioactivity screen

Cell viability (When Appropriate)

ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)

Calculated properties CLogP

PSA

Molecular Weight

rotatable bonds

H-bond donors and acceptors

permeability

pKa

Solubility

TIER 1B

Confirm EC50 determinations for actives compounds in primary screen with fresh

compounds from the original stock Confirm EC50 determinations for the lead (most

active) compound in primary screen with a new sample either repurchased purified

and characterized in-house or independently synthesized in-house

Compounds with IC50s (EC50s) less than X advance to Tier 2

TIER 2A ndash Activity Confirmation

Secondary screen

TIER 2B

Repeat EC50 determinations for actives in secondary screen with fresh

compounds from the original stock



TIER 3 ndash Drug-like Properties Specificity

IC50 selectivity in selectivity screen

CYP450 Inhibition competitive and time-dependent if structural alerts exist

(spot check illustrative examples from compound series)

Measured solubility

Measured protein binding (spot check illustrative examples from

compound series)

Test of Permeability in vitro permeability [indicate assay eg Caco2 orand

PAMPA] (spot check illustrative examples from compound series)

hERG

Cytoxicity assays

All compounds with no significant issues (Define Minimum Conditions for

Advancement) to advance to Tier 4


TIER 4 ndash Scale-up Synthesis and Preliminary PK

Scale-up synthesis

Purity determination gt98 with no single impurity gt1

Rodent bioavailability and PK (define target delivery route) Tmax

Cmax

AUC

Bioavailibility

Vss CL T12 MRT

Brain to Plasma ratios

P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a

Plasma Protein Binding (species)

Microsomal Stability ndash rodent and human

Defineplan Patent Protection Strategy

All compounds with no significant issues (Define

Minimum Conditions for Advancement) advance

in parallel to Tiers 5AampB


TIER 5A ndash In Vivo Bioactivity

Animal efficacy

Validate Biomarker

Target engagement

Advance to Tier 6 if (Define Minimum Conditions for advancement)

TIER 5B ndash Advanced Drug-like Properties

Microsomal stability in multiple

species

Chemical Stability

CYP450 induction

CYP reaction phenotyping

Metabolism ndash human

hepatocytesmicrosomes

Metab ID define major human rat dog and

non-human primates (NHP) metabolites

In vitro Tox Ames

Chromosome Aberration

CNS effects


TIER 6 ndash Liability Assessment

Broad Pharmacological Profile and Toxicology

PK in second species

TIER 7

Non-GLP exposure studies single and multiple dose

Advance to late stage pre-clinical development (Define Minimum

Conditions for advancement)


Principal InvestigatorProgram Director (Last First Middle)

enspenspenspenspensp

THROUGH

PERSONNEL

DOLLAR AMOUNT REQUESTED (omit cents)

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

PrincipalInvestigator

SUBTOTALS

CONSULTANT COSTS

EQUIPMENT (Itemize)

SUPPLIES (Itemize by category)

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

ALTERATIONS AND RENOVATIONS (Itemize by category)

OTHER EXPENSES (Itemize by category)

SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD

CONSORTIUMCONTRACTUAL COSTS

DIRECT COSTS

FACILITIES AND ADMINISTRATIVE COSTS

TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD

main menu

Target identification and Validation resources

Drug targets for human disease emerge from basic research into mechanisms of disease biology Validated molecular drug

targets require that the project team address issues related to Rationale Druggability Mechanism and Safety The

Commercial viability of the approach may also be critical for recruiting industry partners at key junctures to support

development

The Molecular Target is the protein that will bind directly to the proposed drug A validated target has

Rationale

A human genetic or pharmacological link to a selected disease population

bull Modulation of the target has been shown to produce therapeutic benefit in an in vivo animal model of the disease

population or of the relevant circuit dysfunction using a directly translatable and quantifiable endpoint

Druggability

bull A tool compound exists to modulate the target or a family member

bull Biochemical and cellular assays exist to support development of SAR for on-target and off-target activities

Well-Defined Mechanism of Action

bull A clear set of laboratory objectives that specify required mode and degree of target engagement needed for

efficacy

bull Pharmacodynamic measures of target engagement are available to monitor activity in animals and people

bull Disease induced changes in target expression or distribution have been examined

bull Common human SNPs in target documented and functional consequences considered

Safety Risk Assessment

bull Known pharmacological risks associated with target mechanism are documented

bull The tissue distribution of the target is understood in preclinical species humans and patients

bull The most likely off-target activities associated with closest sequence homology are identified and considered for

safety risks

Commercial Potential

bull Competitive differentiation strategy suggests improvement over standard of care

bull Viable intellectual property and product development plan

ACRONYMSampTERMpdf

httpwwwbrainspanorg

wwwnextbiocom

main menu

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

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Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

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Page 98

Button 111

Page 1

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Page 76

Page 87

Page 98

MOUSE OVER

Page 1

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Page 21

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Page 43

Page 65

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Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

ACRONYMSampTERMpdf

httpwwwbrainspanorg

wwwnextbiocom

main menu

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

ACRONYMSampTERMpdf

httpwwwbrainspanorg

wwwnextbiocom

main menu

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

wwwnextbiocom

main menu

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

main menu

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

screening-facility

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

family

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

main menu

disease

and discovery

these resources

main menu

compounds

main menu

(2015)

519 (July 2011) | doi101038nrd3480

main menu

Glossary of Terms

main menu

TNC e-mail lists

ACRONYMS

properties

and NDA

Boston

Dallas

Delaware

New York

San Diego

Silicon Valley

Twin Cities

Washington dc

By J Peter Fasse

P ER SP EC T I V E

PHARMACOK INET I CS

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

Therapeutic

studies

analyzed

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

nloaded from

P ER SP EC T I V E

sciencemagorg

ownloaded from

Editors Summary

Article Tools

Related Content

sciencemagorg

nloaded from

__________________________________________________________________________________________________________________

PROJECT TITLE

__________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

__________________________________________________________________________________________________________________

Background

characteristics

middot

es and are not

middot

projects

Eligibility

s in support of

Budgets

Grants wi

er the

collaboration

Submission

Applicants are

advance

Questions should be

characteristics

projects

collaboration

absorption

blind study

same patient

participate

while it is ongoing

condition

Study launch

Explore resources

Harvard Catalyst

Complete training

CITI training

Rocco Anzaldi

Draft a protocol

Protocol guidelines

Study personnel

Bio Bank

TransLab

securing funding

for clarification

DSMPDSMB

Documents and Tools

ClinicalTrialsgov

Development Office

IRB approval

(CRFs)

CRF guidelines

documents

Confirm study drug

in pharmacy

Rocco Anzaldi

Updated protocol to

nurse manager

Data storage

MOO Guide

meeting

Fernando Valles

Informed Consent

Consent library

Patient flow

1 Seek permission

2 Screenenroll

patients

5 Send Study

6 Collection of

adverse events

7 Study

Annual IRB Report

Write Abstract

raquo Publication

Analysis

Data Entry

Cleaning

Maureen Samson

Retrieve specimen

Mark Kellogg

Biorepository

CRC Request

Complete training

CITI Training

Draft a protocol

Protocol Guidelines

IRB Application

CRF Guidelines

IRB Review





























Next Page

Page 1

Page 119

Page 21

Page 32

Page 64

Page 75

Page 86

Page 97

Button 110

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

Button 111

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

MOUSE OVER

Page 1

Page 1110

Page 21

Page 32

Page 43

Page 65

Page 76

Page 87

Page 98

COVER BUTTON

Previous Page

Page 118

Page 2

Page 31

Page 63

Page 74

Page 85

Page 96

Page 1

Button 91

Button 92

Button 94

IRB review

Button 102


Button 136


INDIDE 1

Explore resources

Button 1016

Bio Bank p

4



Study personnel

Complete training


Draft a Protocal 2


Next Page 1

Previous Page 1

TransLab


Develop study logs

Updatedd protocol

Confirm study drug


COnsult programmer

Clarify system



MOO


Button 44



Data storage

Confidentiality

Blood volume 3

Develop fast fact

Consult MDs

Schedule weekly

Communicate early

Button 71



Datetime tests



Button 77

Dissemination

Button 87

Button 124

Button 125


Button 106

Button 109

Button 1010

Shipping page 9

Button 1012

Button 99

Button 133

Button 134

Button 135

Biorepository


Retrieve specimen

Button 30

Consult office

Negotiate Contract

Organizing DSMB

Submit Grant


Button 66




Blood volume 2



clinicaltrials

gov

BPN Project


Tier 1 2 3

Tier 6 7 8

Tier 5

Tier 4


Cytotoxicity

Grant

Project








PSA

Molecular Weight

rotatable bonds


permeability

pKa

Solubility

TIER 1B







Secondary screen

TIER 2B









Measured solubility


compound series)



hERG

Cytoxicity assays





Scale-up synthesis



Cmax

AUC

Bioavailibility

Vss CL T12 MRT











Animal efficacy

Validate Biomarker

Target engagement




species

Chemical Stability

CYP450 induction






In vitro Tox Ames


CNS effects





TIER 7





THROUGH

PERSONNEL

ROLE ONPROJECT

TYPEAPPT (months)

EFFORTONPROJ

INSTBASESALARY

SALARYREQUESTED

FRINGEBENEFITS

SUBTOTALS

CONSULTANT COSTS

TRAVEL

PATIENT CARE COSTS

INPATIENT

OUTPATIENT

DIRECT COSTS

Documents

Preclinical Road map for Neuroscience Drug Discovery

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY

image1jpeg

image2emf

DETAILED BUDGET FOR INITIAL BUDGET PERIOD

DIRECT COSTS ONLY