CHAPTER 19

Look AHEAD-E Ancillary Study Policy

19.1Definition...... 19-2

19.2Role of Substudies and Ancillary Studies (SAS) Committee...... 19-2

19.3Ancillary Study Review...... 19-2

19.4Outside Funding Required for Ancillary Studies...... 19-3

19.5Scientific Review of Ancillary Studies...... 19-3

19.6IRB Approval...... 19-4

19.7Confidentiality...... 19-4

19.8 Industry-Sponsored Ancillary Studies...... 19-4

19.9Procedure for Proposing an Ancillary Study in Conjunction with

Look AHEAD-E...... 19-4

19.10Timeline for Submitting Ancillary Study Proposals...... 19-5

19.11Data Issues...... 19-6

19.12Publications and Presentations...... 19-6

Appendix A: Coordinating Center Fee Schedule for Providing Non-Look

AHEAD-E Investigators with Look AHEAD-E data for Ancillary

Studies...... 19-7

Appendix B: Look AHEAD-E Ancillary Study Proposal Template...... 19-9

Appendix C: Request Letter for Transfer of Ancillary Study Data to Coordinating

Center...... 19-14

19.1 Definition

InLookAHEAD,an ancillarystudyis definedasonethat derives support from sources

otherthan the cooperativeagreementgrant fundsawarded byNIHforsupport of themain trial.

An ancillarystudy's objectives arenot duplicativeof and do not interferewith theLook AHEADparent studybut useLookAHEADparticipants, samples, ordata collected by Look AHEAD.

Look AHEAD represents a largeand uniquelywell characterized population sampleof obeseindividuals with type2 diabetes.To makethebest possibleuse of this extraordinaryresource,Look AHEAD encouragesinvestigators to develop ancillary studies in conjunction with thetrial and to involve other investigators, within and outside ofLookAHEAD, in thisprocess.Anancillarystudymayinvolvedata collection from oneor moreLookAHEAD Centers foroneor more cohorts.

19.2 Role ofSubstudies andAncillary Studies (SAS) Committee

TheSteeringCommitteemust approve all ancillarystudies to ensurethat theydo not

impose an unacceptableburden to staff or participants or conflict with the aims ofLook AHEAD.TheSteeringCommitteedesignates theSASCommitteeto conduct a preliminaryreview ofallproposed ancillarystudies. Data collection maynot proceed without the approval of theSAS Committee.

IfanySAS member proposes an ancillarystudy,collaborates with an investigator who proposes an ancillarystudy, or is affiliated with theinstitution of an investigatorwho proposes an ancillarystudy, heor shewill be recused from consideringthatancillary studyproposal, similar to NIH peer reviewpolicies foravoidanceofactualorperceived conflicts of interest.

19.3 Ancillary StudyReview

TheSAS Committeewillconductapreliminaryreview and providerecommendations to

the SteeringCommitteefor approval ofancillarystudies concepts through theprocess described in this chapter. Proposals will be assessed to evaluatewhethertheywould interferewith other parts ofthe protocol, would hampercontinued recruitment or participation inLookAHEAD-E, or would be inconsistent with theLook AHEAD-Eaim of facilitatingabroadrangeof research.

Ifan ancillarystudyproposal meets thetest of non-interferencewithLookAHEAD-E, it maystill competewith other proposedancillarystudies forlimited additional participant orstaff time and/or biological resources (e.g., blood).To maximize efficiency, the SAS recommends that several similar and potentiallycompetingproposals becombined.

Highest prioritywill begiven to studies which best fit the following criteria:

  1. Havethe highest scientificmerit.
  2. Do not interfere with or duplicatethe mainLook AHEAD-E objectives.
  3. Producethe least burdenonLook AHEAD-E participants and theleast demand onLook AHEAD-Eresources suchas blood samples
  4. Requirethe unique characteristics oftheLook AHEAD-Ecohort
  5. Contributeto the aim of examiningabroad rangeof research questions.

Ifa changeoccurs in thedesign orconcept of theancillarystudyafter it has been approved, theSAS committeeshould benotified.TheSteeringCommitteewill be asked to approvethe alterations, based onthe recommendation ofthe SAS Committee.

TheDataand SafetyMonitoring Board (DSMB)mayalso be askedto judgethedemands the proposed studyplaces on participants and thepriorityin relation toLook AHEAD-E objectives.

19.4 Outside Funding Required for Ancillary Studies

Investigators proposingancillarystudies must seek fundingfrom outsidesources to

conduct their research. Examples include funding obtained through investigator-initiated NIH researchgrant awards (R01s), grants from academicinstitutions,orprivate sources (e.g., drugcompanies, non-profit health organizations).

Inassessingthe acceptabilityofan ancillarystudyproposal, the SteeringCommitteewill be concerned with both the explicit and the hidden costs toLook AHEAD-Eentailed bythe proposal (e.g.,costs to theCoordinatingCenter for coordinatingthe additional data collection, costs to Clinical Centers fornotification of alert values).ThePI ofthe ancillarystudyshould provide evidencethat adequate support forcarryingout these functions is available at his/her institution;if not, theCoordinatingCenterwill conduct the activities required usingresources that must be included in the ancillarystudybudget. (See, “Look AHEAD-E ReimbursementCosts”fordetails of the general policyfor charges in providinginvestigators withLook AHEAD-Edata,Attachment A.)

19.5 Scientific Review of Ancillary Studies

Forproposals submitted to theNIH, either in response to an RFA or as investigator-

initiated R01 applications, scientificreview is through theregular NIH peer review system. For other proposals, if no otheracceptablepeerreview has taken place, thescientificmerit of aproposal will be reviewed bythe SAS, supplemented with additional experts as necessary.

19.6 IRB Approval

All ancillarystudies must receive necessaryapprovals fromIRBsat theindividual

institutionsinvolved. Documentation ofIRB approval is required to be submitted to the Look AHEAD-E CoordinatingCenterbefore anancillarystudycan beinitiated in conjunction withLook AHEAD.

19.7 Confidentiality

Confidentialityof individuallyidentifiable data aboutLook AHEAD-Eparticipants must beassured. Look AHEAD-E provides no assurances that ancillarystudies will be able to identifyandcontact participants in the future, particularlyafterLook AHEAD-E ends.

19.8 Industry-sponsored Ancillary Studies

Proposals for industry-sponsored ancillary studies are evaluated in accordance with the Look AHEAD-E procedures used for all other ancillary studies. As in all ancillary studies, conduct of industry-sponsored ancillary studies must comply with all existing Look AHEAD-E and NIDDK practices and guidelines. This includes the stipulation that all data relevant to the ancillary study must be submitted and shared with the Coordinating Center and the Steering Committee.

In addition, for industry-sponsored Ancillary Studies, it is the responsibility of the PI to work with the Coordinating Center and the sponsor, NIDDK, to obtain agreement with the industry sponsor describing how all data, biospecimens, and results will be used and how all publications will be developed. NIDDK practice includes the following requirement: that the industry sponsor (recipient) also must agree not to use material for any commercial purposes to include selling, commercial screening, and manufacturing.

19.9 Procedure for Proposing an Ancillary StudyinConjunction with Look AHEAD-E

Each ancillarystudymust include a Look AHEAD-E PrincipalInvestigatororCo- investigator orInvestigator,(orat minimum the PrincipalInvestigator must endorsetheproject).Theinvestigator on theproposal must also be approved bytheNIHandLook

AHEAD-EExecutiveCommittee and must havetheapproval of thePrincipalInvestigatorat eachLookAHEAD-Esiteproposed. ThePrincipalInvestigator oftheancillarystudyis responsible forsubmittingthe studyproposal to the SAS Committee, monitoringthe studyto ensure continuingcompatibilitywithLook AHEAD-E, and servingas a liaison to theLookAHEAD-ESteeringCommittee, including attendance as requested at SAS and SteeringCommitteemeetings

The“Look AHEAD-E Ancillary Study Proposal Template”(see AttachmentB) must be completed and submitted to Carrie Williams () at the Coordinating Center and the Chair of the Ancillary Studies Committee, Helen P. Hazuda, PhD (). To assess the proposal, theSAS and SteeringCommittees needto know what additional information will be collected at anyof the Look AHEAD-Eclinic visits, the expected burden to participants, and theamount of timeneeded to complete themeasurement. IfLook AHEADcoredata, staff,and/or analysesareneeded fortheancillarystudy, this information should be provided.

The“Look AHEAD-E Ancillary Study Proposal Template”should be filled out beforesubmittinganapplication for fundingto a fundingagency. The proposal willbe reviewed duringoneof threepredetermined cycles, as agreed upon bytheSteeringCommitteeand in correlation with theNIH submission cycle (seeTimelinebelow).DuringtheSAS reviewprocess, theinvestigator maybe askedtorespond inwritingtoconcerns that mayariseduringreviewprocess.An approval bythe SAS committeewillnot be concluded until the concerns aresatisfactorilyaddressed. After SAS approval, theproposal will next requirea final voteand approval bythe SteeringCommittee.Once approved, the PrincipalInvestigatorwill receivean official letter from theSAS Committeesigned byeither theChair oftheSAS Committeeor theCoordinatingCenter representative on this Committee. A copyof thefinal funded proposal should be submitted to the SAS Committee.

19.10 Timeline for SubmittingAncillary StudyProposals

AncillaryStudyProposals will be accepted during an establishedSAS cyclethat

correlates with the NIH cycle, which is threetime periods in a calendaryear. Basically,ancillarystudyproposalsshould besubmitted to theSAS 8 weeks priortothe quarterlyNIH cycle.

Correlating NIH submission dates withLook AHEAD-ESAS Committeeareas follows:

NIH submission deadlineAncillaryStudies CommitteedeadlineJune5 April5

October5August5February5December5

When submissions are received bythe SAS in irregularintervals, i.e., additional reviewsforapplications respondingtospecific RFA’s, thesesubmissions should bereceived bythe SAStwo months priorto thepublisheddeadline.With the receipt of these applications, the SAS committeewill determinethe feasibilityof a timelyreview process, takinginto account therequirement that both the SAS and SteeringCommittees arerequired to give approval.

Submissions involvingaccess to stored samples will be reviewed onetime peryearanddueon April 5. TheSAScommitteerecommends that thestudy groupshould require all assays be conducted at theCentralLaboratory, unless specialtyanalysis is not available at thelab.

19.11 Data Issues

Thereleaseofany LookAHEAD-Edata from the CoordinatingCenter to anancillarystudyinvestigator is subject tothe rules regardingreleaseof data defined in theLook AHEAD-E Publications Policy. TheCoordinatingCenter will establish a projectedcost fordata they areasked to provideto theInvestigator(s) and notifyher/him ofthe charges. The CoordinatingCenter will releasethe requested data at which timepaymenthas been received. SeeAttachment A forthe Table ofCharges.Data collected bythe ancillarystudymust beprovided electronicallyto theLook AHEAD-ECoordinatingCenterforintegration into the main database. In return, ancillary studyinvestigators receive an analysis filecontainingtheirdata andapproved data from the main study.The ancillarystudyPIisgiven the first opportunityto analyze, present, and publish data collected forthe specificaims ofthe ancillarystudy.

Afterareasonable time (in general, 18 months after theancillarystudyPIhas received the cleaned data), the ancillarystudydataaremade availableforadditionaluses by Look AHEAD-Einvestigators, incollaboration with the ancillarystudyinvestigators. It is the responsibilityof theancillarystudyPIto state in writingin advanceto theSteering Committeeanyspecial circumstances that wouldmitigate against these guidelinesfor data sharing.Reasonableand justified requests forlimitingSteeringCommitteeaccess to the data will be considered. (See“RequestLetterforTransfer of AncillaryStudyData to CoordinatingCenter”,Attachment C.)

19.12 Publications and Presentations

Proposals must be submitted forall publications, presentations and abstracts from an

ancillarystudyforreview and approval bythe Publications Committeepriorto submission or presentation, in accordancewith thegeneralrules forpublications and presentations.

Each manuscript and abstract is generallyexpected to include a Look AHEAD-E investigatoras co-author,except undercircumstances that should bestatedand justified as part of theoriginal submission to the SASCommittee.

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Chapter 19 Ancillary Studies – August 2016

Appendix A

Coordinating Center Fee ScheduleforProviding Non-Look AHEAD-EInvestigatorswith LookAHEAD-E data forAncillaryStudies

January 2016

Background:TheLookAHEAD-Estudy hasgeneratedsubstantialdatathatmayserveasresourcesforancillarystudies.CurrentfundingisfocusedontheconductofLook AHEAD-E.Providingdataandsupportforancillarystudiesinvolveseffortthatindividuallymayappeartobemodest,butwhichaddedtogethercanover-taxtheresources of the Coordinating Center.LookAHEAD-Ehasdevelopedageneralpolicyregarding fees that must be included inancillarystudies that utilize Look AHEAD-E data.The following table provides a description of charges that must be included in grant applications to support Coordinating Center activities for grants submitted beginning March 1, 2016.

TableofCharges / CostCategories
SimpleRequest / ModerateRequest / AdvancedRequest
Datasetpreparation / $10,000 / $15,000 / $20,000
Summarytablepreparation for a meta-analysis / $5,000 / $10,000 / $15,000
Receivedata,archive,trackanddistributetoPIs / Required of all studies; no additional charge.

TheLookAHEAD-ECoordinatingCenterwilldetermine the category ofthedatasetorrequestandwillincreasechargesappropriatelyforlargeorcomplicateddatasetsoranalyses.Thefollowingisaguidelinefordeterminingrequestcostcategories:

  • Simple=onevisit,100variables(variablesoutlinedwithLookAHEAD-Evariablenames)
  • Moderate=multiplevisitsand/oroutcomedata100variables(variablesoutlinedwithLookAHEAD-Evariablenames).
  • Advanced=multiplevisitsand/oroutcomedata100variables.

Exceptionscanbemade(upordown,includinghigherthanthe"advanced"level)bytheCoordinatingCenter,asdeterminedbytherequest.ConditionstoconsiderareiftheCoordinatingCenterhastodevelopanIRBapplicationorreport,createderivedvariables,ordootheradministrativetasks.

Contact person:Carrie Williams(Project Manager)

WakeForest Health Sciences Departmentof Biostatistical Sciences Medical Center Boulevard

Winston-Salem, NC27157

Phone: (336)716-6321

Fax: (336) 713-5249

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Chapter 19 Ancillary Studies – August 2016

Appendix B

Look AHEAD-E ANCILLARY STUDY Proposal Template

(02/06/2014)

The following areas are to be addressed in the proposal. The proposal is limited to 5 pages or less (using 11 point font). Submit your proposal to Carrie Williams () and the Chair of the Ancillary Studies Committee, Helen P. Hazuda, PhD ().

NOTE: The submission is to be received at least 3 months in advance of any planned grant submission deadline. Submissions received <3 months in advance are not guaranteed to be reviewed and a decision made prior to the grant submission deadline.

  1. Date:
  1. Title of Ancillary Study:
  1. Principal Investigator:

Institution:

Address:

E-mail Address:

Phone Number:

  1. Look AHEAD-E PI who is a Co-Investigator on this Project:
  1. Additional Co-Investigators and E-mail Addresses:
  1. Science Background, Rationale, Significance:
  1. Main Hypothesis, Aims:
  1. Methods:
  2. Existing data you anticipate requesting
  3. If requesting biological samples (stored blood), provide details on the number of samples, time periods requested, amount of sample to be used, and details on how the samples will be used.
  4. New data you anticipate collecting
  5. Sample size and power justification
  1. Burden (include plan to support burden and costs):
  2. Participants
  3. Clinic
  4. Coordinating Center
  1. Resources
  2. State clearly any resources you may need from the Coordinating Center (limited to data transfer from WFUHS)
  3. State clearly any identifiable needs from the clinics
  1. Safety:
  2. Risk to participants
  3. Steps to mitigate or minimize
  4. Complete the Look AHEADAncillary Study DataMonitoringSafetyForm (below)
  1. Funding Mechanism:
  2. Granting agency
  3. Submission Deadline
  4. RFA/PA is applicable
  1. Cost for data analysis by Coordinating Center

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Chapter 19 Ancillary Studies – August 2016

AncillaryStudy-DataSafetyMonitoringReportRequest

April 30, 2010 - 1stRevision

March 23, 2007 -Original

The Look AHEAD SafetyCommitteerequests fromyou areport about new data already developed (or to bedeveloped)inyour AncillaryStudy. TheSafetyCommitteeadopted this safetyreportingprocedurein March 2007.

Thereport should includethe following:

(1)alist of all new variables developed byyourAncillaryStudy;

(2)your reasoningaboutwhich of thesevariablesarepossiblymeaningfulclinically; and

(3)your plans to report clinicallymeaningful results back to participants and their physicians. This information could be provided in the form of atable and abrief cover memo (seemodel table attached). ThecompletedData Table with brief cover letter should besent to theattentionof Ms. Carrie Williamsat theCoordinatingCenter.

Case that OriginallyPrompted this Request

Thecaseinvolves an NIHfunded ancillarystudythat involves questionnaires andstored

blood samples. Thegoalof thestudyis to studybiomarkers ofoxidative stress in relation to weight loss. ThestudyPIand thelocal site PI’s all judged that the biomarkers of interest wereso novel asto not warrant reportingto participants or their physicians. However, to accuratelyestimatebiomarker levels,the protocol required measurement of circulatingimmunoglobulins-IgG,IgM, andIgA. Theseweremeasured onstored specimens, months after thespecimens weredrawn. Afterthe studyhad been in the field forseveralyears, the followingquestion arose: How should theimmunoglobulin levels is addressed? Unlike thebiomarkers that werethe focus of thestudy, thesewereclinically available assays that could beimportant.Forexample, veryhigh levels ofIgGcould indicate an underlyingbonemarrow cancer.SinceHopkins was oneof the clinical sites involved, wehad to deal with this question directly. Our judgment was that, although most immunoglobulin level ‘abnormalities’arenon-specific(e.g. dueto transient infection orgeneticvariation) and hencenot usedforscreeningin standardpractice; we should nonetheless investigate thedata, with particularattention to markedorprogressive abnormalities, and reportthose back to participants and physicians,couched in appropriatelynon-alarmist language.

Deliberations of Safety Committee

Thecasein point above was addressed locally. TheSafetyCommitteedeveloped astudy-

wide response, to reducethe likelihood that other ancillaryPIs and clinic PIs would be surprised byasimilar circumstance?

Thecommitteeformed consensus around the followingopinions:

(1)the Parent Studyalreadyhasadequatemonitoringandreportingmechanisms in place forclinicallyrelevant datadeveloped in ‘real time’ (e.g. ECG, GXT, DEXA, A1c, lipids, BP, etc.);

(2)the parent studyshould consider monitoring and reportingconcerns as data are developed from banked specimens (e.g. serum, DNA);

(3)individual AncillaryStudies might not be as well prepared as the ParentStudy, especiallythose that relyon delayed assayof banked specimens;

(4)data monitoringand safetyin AncillaryStudies is inherentlytheresponsibilityof the AncillaryStudyPIand their collaboratingPI’sat Look AHEAD clinics, under the direction of therelevantIRBs; and

(5)the role of the LookAHEADSafetyCommitteevis a vis the AncillaryStudies should not be to micro-managedata monitoringandreporting, but rather to insure that such plans arein place andappear reasonable.

Considerations inWriting Report

With opinion #5in mind,the SafetyCommitteerequests abriefreport from each

AncillaryStudyPIregardingdata monitoringandsafety.Pleaseusethe form included and keep thefollowing considerations in mind:

Data AlreadyDeveloped

You should alreadybe actingon aplan for monitoringandreportingalreadydeveloped data thatyou consider‘clinicallysignificant’. Ifyou’renot sureabout clinical significanceafterreading this memo and completingthe form, theSafetyCommitteeis glad to helpyou deliberate.

Data You Plan to Develop

These aredatayoualreadyspecifiedinyour approved AncillaryStudyproposal, butyou haven’t developedyet (e.g. assays on banked specimens).

Typeof Data

Useyour judgment in terms of lumping.Forexample,you might show “complete blood count” rather than listingindividual components.But pleasesplit whereyou think questions might arise. For example, forheavymetals,you might lump arsenic, mercury, and lead together as recognized toxins that requiremonitoringand split out chromium, selenium, and zinc as traceminerals of uncertainsignificancethat do not require reporting.

ClinicallyRelevant?

Please consider this carefully. In the trigger case,noneof theinvestigatorsconsidered serum immunoglobulins as ‘clinicallyrelevant’ because they’renot usedfor screening purposes in primarycare. But, upon morecarefulconsideration, the committeethought it was possiblethat an abnormal result could be a clueto an underlyingmalignancy. It is likelythat most tests donein clinical laboratoriescould havesome clinical relevance, even if onlyin selected individuals. For example, fastinginsulin level is not typicallythe object of medicalattention. However, highlyelevated fastinginsulin could indicate the presenceof an insulinoma. Ifyou’renot sure, pleaseposethe question to theSafety Committeeand theywillgiveyou theirconsensusadvice.

Ifrelevant, how doyoumonitor and report? (or fordatayet to developed,how willyoumonitor and report?)

Here, thecommitteewould likeyou to saysomethingabout time frame, who reviews, and somethinggeneral about howyou flagabnormal results.At this point, keep it brief. Theywill follow up withyou if needed to know moredetails.

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Chapter 19 Ancillary Studies – May 2016

Look AHEADAncillary Study DataMonitoringSafetyForm

March 31, 2010Form/Please andfill out usingMS Wordandaddmorerows andspace as needed

If you’refillingthis formout as part ofa‘new AncillaryStudy’ application, thenpleaseignorethe‘data alreadydeveloped’ section

Today’s Date:

Name ofAncillaryStudy:

AncillaryStudyPI:

CollaboratingLookAHEADSites:

TotalNumberof Participants:

TypeofData / Clinically
Relevant?(Yes,Maybe,No) / Does your
consentformcommentaboutmonitoringorreporting?(Yes,No) / Ifclinicallyrelevant,howdo/willyoumonitorandreport?
DataYou’veAlreadyDeveloped
DataYouPlantoDevelop

Comments:

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Chapter 19 Ancillary Studies – 12/05/2017

Appendix C

Request LetterforTransfer of AncillaryStudyDatato CoordinatingCenter

Date:

To:Ancillary StudyPrincipal Investigator Re:

LookAHEAD-E Ancillary Study:

Dear:

The LookAHEAD-E Coordinating CenterissolicitinghelpfromLookAHEAD-E Ancillary StudyPrincipal Investigatorstofacilitatethetransferoftheirdatatoourcentralarchive ofstudydatabases.Asyou’ll recall,ancillarystudiesaresubjecttodata transfer requirements,which waspartofyouragreementwith theLookAHEAD-E studygroup.This requirementisoutlined in theAncillary Studies Policydocument(see excerptfromthe policybelow).

Wehave determinedthatthedatatransfercanmosteasilybe accomplished ifthe datafile issaved in astandardfileformatsuchas.xlsor.csv.Thedatadictionary should accompanythe datasothatwe will be awareofanyvariables thatmayhave been created. Ms.Lea Harvin ()will coordinateourefforts. Wearerequesting thatyou orone ofyourstaffplease contactMs.Harvin inthenextfew weekstoinitiatethe process ofdatatransfer.Wealso requestthatyou send confirmationto Ms.CarrieWilliams()thatyou have either previouslytransferred yourdata oryou have made initial contactwith Ms.Harvin to arrangethedatatransfer.