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Guidance for IRBs Clinical Investigators and Sponsors Considerations When Transf

S Department of Health and Human Services Food and Drug Administration Center for Drug Evaluatio n and Research Center for Biologics Evaluation and Research Center for Devices and Radiological Health Office of Good Clinical Practice May 2014 Contains

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Guidance for IRBs Clinical Investigators and Sponsors Considerations When Transf




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Guidance for IRBs, Clinical Investigators,andSponsorsConsiderations When TransferringClinical Investigation Oversight AnotherU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research Center for Biologics Evaluation and Research Center for Devices and Radiological Health Office of Good Clinical Practice May ��Contains Nonbinding RecommendationsGuidance for IRBs, Clinical Investigators,andSponsorsConsiderations When TransferringClinical Investigation Oversight AnotherIRBAdditional copies are available from:Division of Drug Information, WO512201Office of CommunicationCenter for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave.Silver Spring, MD 20993002http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm Email: DRUGINFO@fda.hhs.gov (Tel) 3017963400; (Fax): 3018478714and/orOffice of Communication, Outreachand Development, HFM40 Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike Rockville, MD 208521448 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm Email: ocod@fda.hhs.g (Tel) 8008354709 or 3018271800and/orDivision of Industry and Consumer Education, WO665429Office of Communication, Education and Radiation ProgramsCenter for Devices and Radiological HealthFood and Drug Administration10903 New Hampshire Ave.Silver Spring, MD 20993002http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm Email: DICE@cdrh.fda.gov (Tel) 800.638.2041 or 7967100U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research Center for Biologics Evaluation and ResearchCenter for Devices and Radiological HealthOffice of Good Clinical Practice May ��Contains Nonbinding RecommendationsTABLE OF CONTENTSINTRODUCTIONII. BACKGROUNDIII. WHEN OVERSIGHT OF A PREVIOUSLY APPROVED CLINICAL INVESTIGATION TRANSFERS FROM THE ORIGINAL IRB TO ANOTHER IRBNOT PART OF THE SAME INSTITUTIONIV.SPECIAL SITUATIONSA. Transfer of IRB Oversight from one IRB to Another IRB in the Same Institution and Temporary Transfer of IRB Review ResponsibilityB. Transfer of a Clinical Investigation to a New Research Site Requiring IRB ReviewV. ADDITIONAL QUESTIONSABOUT TRANSFERRING OIGHT OF A CLINICAL INVESTIGATI ��Contains Nonbinding Recommendations 1 Guidance for IRBs, Clinical InvestigatorsandSponsorsConsiderations When TransferringClinical Investigation OversightAnotherIRB This guidance representthe Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. INTRODUCTIONThis guidance discussestheregulatory responsibilitiesof institutional review boards (IRBs)clinical investigators, and sponsorswhenoversight of previously approved, ongoingclinical investigationunder FDA’s jurisdictionis transferredfrom one IRB to another IRThis guidance also addresses questions that have beenpreviouslyraisedconcerning procedures and processes that are required and/or recommendedby FDAwhen such oversight is transferred. FDA encourages individuals to contact the agency directlyto discuss any unusual circumstancesTo enhance human subject protections and reduce regulatory burden, FDA and the Office for Human Research Protections (OHRP) have been actively working to harmonize the agencies' regulatory requirements and guidance for human subjects research. This guidance document was developed as a part of these efforts.For studies subject to 45 CFR part 46 (i.e., studies that are funded, conducted, or supported by the Department of Health and Human Services), OHRP issued a draft guidance entitled, “Considerations in Transferring a Previously Approved Research Project to a New IRB or Research Institution.”FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use the word shouldin Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND This guidance has been prepared by the Office of Good Clinical Practice, Office of Medical Products and Tobaccowith input fromthe Center for Drug Evaluation and esearch (CDER), Center for Biologics Evaluation and Research (CBER) and Center or Devices and Radiological Health (CDRHat the Food and Drug Administration. OHRP’s guidance is available at: http://www.hhs.gov/ohrp/newsroom/rfc/transferdraftdoc.html . ��Contains Nonbinding Recommendations 2 An IRB is any board, committee, or other group formally designated by an institutionto review,approve the initiation of, and conduct periodic review of biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects.To prevent lapses in human subject protection, it is generally preferred that the same IRB retain oversight responsibility throughout the conduct of the trial, if possible. FDA recognizes, however, that clinical investigationsthat were originally approved by IRB aresometimestransferred to another IRB for subsequent review and oversight. These transfers may give rise to a number oflegal, regulatory, administrative, and logistical considerationsfor the parties involvedThe research entities involved in a transfer of IRB review responsibilities for a clinical investigation include:The originalIRB, which for the purpose of this guidance means the IRB originally designated to review a clinical investigation andthat transfers oversight responsibility to another IRB; The receivingRB, which for the purpose of this guidance means the IRB that accepts responsibility for oversight of the clinical investigation; The sponsor who initiates the clinical investigation; andTheclinical investigator who conducts the investigation.transfer of review responsibility for a clinical investigation from one IRB to another should be accomplished in a way that assures continuous IRB oversight with no lapse in either IRB approval or the protection of human subjects, and with minimal disruption of research activities. This guidancediscusses possible actions that sponsors, clinical investigators, and IRBstafffor the original and receiving IRBsshould consider beforeuring, and afterany such transfer.Ideally, IRBs will have their own proceduresand/or institutional policies in place to provide general guidance if oversight of a clinical investigation must be transferred to another IRB.We recommend that the original IRB work closely with the clinical investigator, the sponsor, and the receiving IRB, as appropriate, throughout the transfer process to ensure an orderly transition and continued protection of human subjects. Effective communication among the IRBs, sponsors, clinical investigators, FDAand others (e.g., institutional members, Data Safety Monitoring Board, Contract Research Organization (CRO)) is critical to ensuring a smooth transition to another IRB. FDA recommends that any impending changes in oversight be communicated as early as possible in the transfer process. In some situations, a transfer may disrupt study enrollment or other aspects of a clinical investigation, whether because of unforeseen difficulties in the transfer process or because of concerns arising from the study. FDA believes that providing this guidancewill help to ensure that serious disruptions are rare.FDA’s requirements place the responsibility for securing IRB review and approval on the clinical investigator in clinical investigations of new drugs and biological products,and on the 21 CFR 56.102(g). 21 CFR 312.66. ��Contains Nonbinding Recommendations 3 sponsor in clinical investigations of medical devices.In practice, however, the party that actually initiates the transfer process varies depending on the circumstances necessitating the transfer and the parties involved. For example, an institution’s IRB may decide to transfer oversight for its pediatric clinical investigations to an IRB with such expertise within the same institution. Whoever initiates the transfer of oversight, the clinical investigator and sponsor continue to be responsible for their respective regulatory obligations (e.g., making any modificationsto the informed consent document required by the receiving IRB).Although FDA regulations at 21 CFR parts 50, 56, 312, and 812 do not specifically address the issue of transfer of oversight from one IRB to another, the requirements governing review, oversight, and conduct of clinical investigations applynonethelessWhile this guidanceprovides recommendations to facilitatesuch a transfer, itdoes not create or imply new requirements and/or responsibilities for IRB, sponsor, or clinical investigatorransfers of IRB oversight of clinical investigation may occur for a number of different reasonsincludingcessation of IRB operations, consolidation of multiple IRBs into a single IRB, temporary inability of an IRB to meet its obligations, or as a result of IRB noncompliance. Specific examples include:A medical school decides to transfer oversight responsibility fora category of its clinical investigations (e.g., drug research, device research) to another IRB.A hospital’s IRB realizes it has an excessive workload, but the institution does not want to establish an additional IRB and transfers oversight of some clinical investigations to otherIRB.A large multicampus university decides to consolidate its human subject protection system by closing one or more of its existing IRBs and transfers oversight to aindependentIRB.A small institution has an insufficient number of clinical investigations to justify maintaining its own IRBand decides to cease operations of its IRB and transfer oversight of itsclinical investigations to anotherIRBA sponsor decides to transfer IRB oversight from one IRB to another.Financial or other considerations cause an IRB to cease operations.An institution realizes its current IRBs are overburdened and establishesanother IRB to share the workload.A fire, flood, or other disaster temporarily prevents an IRB from fulfilling its review/oversightresponsibilities.An IRB is subject to administrative actions under 21 CFR 56.120 or has been disqualified under 21 CFR 56.121.A sponsor decides to transfer a clinical investigation when an investigator moves to a new research site. 21 CFR 812.40. See, e.g., 21 CFR 56.109, 21 CFR 312.66, and 21 CFR 812.40.21 CFR 56.121(b) provides that an IRB may be disqualified if FDA determines that the IRB has refused or repeatedly failed to comply with the applicable regulatory requirements and the noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation. ��Contains Nonbinding Recommendations 4 The complexity and duration of the IRB transfer process itself is expected to vary, depending on the reasons for the transfer, the parties involved, and the number and risk of the studies being transferred. For example, transfer of IRB oversight due to purely administrative reasons such as consolidating IRB workloadmay be relatively quick and straightforward, whereas a transfer of oversight due to the original IRB’s noncompliance mightbe lengthierand involvemore complicated legal, regulatory, administrative, and logistical considerations. In general, the type of IRBs involved (e.g., academic, hospitalbased, independent) would not affect the steps to consider when transferring oversight.Section III of this guidance documentprovides recommendations concerning the transfer of IRBoversightfrom one IRB to another IRBthat inot part of the same institution (including independent IRBs). Section IV of this document addresses several special situations:the transfer of oversight from one IRB to anotherIRBoperatingwithin the same institutionthe temporary transfer of clinical investigation oversight to another IRB thatoccurs as a result of a natural disasteror for other reasonsand the transfer of a clinical investigation to a new research site requiring IRB reviewWHEN OVERSIGHT OFA PREVIOUSLY APPROVECLINICNVESTIGATIONTRANSERS FROM THE ORGINAL IRB TO ANOTHERIRB NOT PART OF THE SAMEINSTITUTIONWhen transferring IRB review and oversight of clinical investigations from one IRB to another IRB, FDArecommendthata plan forthetransfer process be documented in a written agreementbetween the original and receiving IRBs, if appropriateThe agreement shouldaddresshow the IRBs should andle, and document as appropriate, thefollowingeight steps.e describe each of these steps in more detail below. Please note, this list is not meant to be exhaustive. Additional actions may be necessary and/or appropriate. (1)Identifying those studies for which IRB oversight is being transferred(2)Ensuring the availability and retention of pertinent records;(3)Establishing an effective date for transfer of oversight, including records, for the clinical investigation(s)(4)Conductinga review of the studyies)by the receivingIRB, where appropriate,before acceptresponsibility for the study(ies); (5)Confirming or establishing the date for the next continuing review;(6)Determining whether the consent formneeds to be revised; FDA encourages the use of central IRBs, in appropriate circumstances, as a mechanism to reduce burden and delays in the conduct of multicenter clinical trials. The goal of the centralized process is to increase efficiency and decrease duplicative efforts that do not contribute to meaningful human subject protection. For additional information relating to the use of central IRBs, see FDA’s Guidance, “Using a Centralized IRB Review Process in Multicenter Clinical Trials,” available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm . FDA recognizes that for transfer of oversight to an IRB at the same institution, a written agreement may not be necessary as the process may be addressed by the institution’s established procedures (assuming all appropriate steps described in Section III are covered). In general, some IRBs may have a policy not to transfer or accept a study until a final transfer contract or similar agreement is signed by both the original and receiving IRBs ��Contains Nonbinding Recommendations 5 (7)Notifying the key parties; and(8)Updating IRB registration information.(1) Identifying those studies for which IRB oversight is being transferred.of the first stepin the transfer process is determining for which studies IRB oversight is being transferred. FDA recommends that he original and receiving IRBs have a clear understanding of this as itill help to bring certainty and continuity to the process and allow for effective planning, particularly when a large number of studies is being transferredThe number of studieshe risk posed by themand the circumstances leading to the transferas discussed belowwill influence subsequent steps in the transfer process e.g., ether records are obtained from the original IRBor the clinical investigator/sponsor, how the transfer date is established, and whether the receiving IRB decides to conduct a review before accepting responsibility for the researchEnsuringthevailability and retention of pertinent ecordsBefore the receiving IRB accepts oversight of the transferred clinical investigation, it should obtain copies of pertinent records to allow it to meet itsreview and ongoing oversight responsibilities for the studyonce transferredPertinent records include documents such as the research protocol and significant amendments; approved consent form; investigator’s brochure; minutes of IRB meetings at which the research was reviewed; reports of unanticipated problems involving risk to human subjects and others; reports of IRBconducted audits, if any;andcorrespondence with the investigator, sponsor, and/or FDA. (a)Availability of pertinent records. With concurrence of the sponsor, the original IRB should make pertinent records available to the receiving IRB.This can be accomplished by providing the receiving IRB with paper or electronic copies of the pertinent records.It is important to note that the sponsors concurrenceis necessary because the records may contain confidential commercial information. Alternatively, the receiving IRB may decide to btain the records directly from the clinical investigator and/or sponsorIf records are obtained in this manner, the receiving IRB should also obtain meeting minutes from the original IRB as this information may be critical to the receiving IRB’s assessment of the adequacy of the previous review (e.g., discussion of controverted issues, quorum, etc)he receiving IRB may choose to obtain records directly from the clinical investigator and/or sponsor Obtaining pertinent records about studies in advance of oversight transfer should help receiving IRBs meet theirprocedural and review obligations for the studies once transfer is complete. For example, under 21 CFR 56.108(a) and (b), IRBs must follow written procedures for certain review activities; these written procedures may be an important resource for determining the records that should be transferred. In some cases, sponsors may not agree to the transfer of records to a proposed IRB. In such cases, he sponsor and/or investigator should work expeditiously to arrange for oversight by another IRB.For more information on creating, maintaining, and archiving electronic records for regulatory purposes, see FDA’s guidance, “Computerized Systems Used inClinical Investigations,” available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070266.pdf ��Contains Nonbinding Recommendations 6 for example,whena transfer occurs as a result of nocompliance actions of the original IRB. Both the original IRB and the receiving IRB should maintain adequate records regarding the clinical investigationaffected by the transferSuch records should includeanywritten agreement between theriginal and receivingIRBsthe title of the protocols being transferredthe expiration dates of IRB approvalthe researchsites affectedthe names of the associatedsponsorclinical investigatorsand Cthe identitiesof the original IRB and the receiving IRBand the date(s)on which the receiving IRB acceptresponsibility for oversight of theclinical investigations. In addition, the originaland receiving IRBshould keep adequate records of all communications to all affected sponsorsclinical investigatorsand FDA, and comply with all other recordkeeping requirements(b)Retention of IRB recordUnder FDA regulations, IRBrecords related to the review of clinical investigationmust be tained for at least three (years after the completion of the researchand the records must beaccessible for inspection and copying by FDAat reasonable times and in a reasonable mannerBecause FDA may require access to the records at any reasonable time, it important for the gency to knowwhetherthe original IRBthe receiving IRB, the institution that housed the original IRB, a CRO or other responsible third party will maintain the recordsonce clinical investigation oversight has been transferredThe partythatassumes responsibility for the records is responsible for ensuring that they are tained in accordance with 21 CFR 56.115(b). As a general matter, the original and receiving IRBs have the flexibility to work out any suitable arrangement for handling the transfer and maintenance of the recordsas long as the records remain accessible for inspectionandcopying authorized representatives of FDA at reasonable times and in a reasonable mannerFor example, the original IRBmay decide to transfer to the receiving IRB the records related to the clinical investigations that are still active and retain the records for closedclinical investigations, or the receiving IRB may choose to receive all of the recordsWhen the original and receiving IRBs agree to share record retention responsibilities, FDA recommends that Under some circumstances (e.g., if the original and transferring IRBs are located at the same institution), FDA recognizes that the records may be stored in a mutually accessible location. Duplication of the study records would not be necessary. If the files are mutually accessible, the IRBs should make appropriate arrangements for viewing and using the files. Under 21 CFR 56.115(a)(4), IRBs are required to keep copies of all correspondence between the IRB and the investigator(s). 21 CFR 56.115(b). IRBs may have their own recordkeeping requirements that supplement FDA’s requirements.If storage space is a concern, the receiving IRB could, for example, scan the records as certified copies of the originals so that they can be stored electronically, as long as the records remain accessible for inspection and copying by FDA. For additional information, see FDA’s guidance, “Computerized Systems Used inClinical Investigations,” available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070266.pdf . ��Contains Nonbinding Recommendations 7 they reach a clear understanding of their respective rolesto avoid confusion and to ensure appropriate responsibility for and access to the documentsThere may be circumstances when the original IRBreaches an agreement with the receiving IRB to retain some of the documentation for the transferred trials, yet may not be able tocommit toretainingthe documents for at least 3years after the completion of the researchFor instance, ifan IRB ceases operations etains responsibility for some records for trials thatare still ongoingeither physically maintaining these records or reaching a storage arrangement with a responsible third partyIn this instance, recommend that theoriginal IRBcontact FDA to discuss possible retention arrangementsIn this situation, the original IRB should make arrangementsto transfer the documents to the receiving IRB or to another, responsible party.) Establishing aneffective date fortransfer of oversight, including records,for the clinical investigation(s).FDArecommends establishingransfer date for each clinical investigation, including records,for which oversight is being transferredAlthough there is no regulatory requirement to establish a transfer date, such an action promotes continuity, helps prevent a lapse in IRB coverage,and minimizes confusion regarding which IRB is responsible for review and action if an unanticipated problem should arise or if the clinical investigation needs to be quickly suspended or terminated.When choosing a transfer date, the affected IRBs should allow enough time for all appropriate actions, communications, and agreements to occur.Depending on the circumstances of the transfer, the transfer date maybe established using one of a variety of methods, such as the following:In thewritten agreement, the exact date is specified in advance between the original IRB andthe receiving IRB; orIn thewritten agreement, the date is made contingent upon thereview andeptance of the clinical investigationby the receiving IRB. For example, if the receiving IRB decides to performinitial review of the clinical investigation, he transfer may take effect on the date the receiving IRB makes its decision approve, require modificationin (to secure approval), or disapprovethe clinical investigationIn this situation,the receiving IRB should notify the originalIRBand other involved partiesof the date of its approval and acceptance of oversightresponsibilitiesNote that if both the original and receiving IRBs are located within the same institution, the transfer date may be determined according to the established procedures of that institution. Factors to consider in selecting an appropriate record retention arrangement may include the reasons forthe transfer, as well as the nature of the clinical investigations and the records. Generallyspeaking, and depending on the specific facts, FDA would expect an IRB that has accepted record keeping responsibilities to retain the documentation for at least3 years after closure of the IRB, in accordance with 21 CFR 56.115(b), or transfer the records to the receiving IRB. ��Contains Nonbinding Recommendations 8 hen a large number of clinical investigations arebeing transferred, it may be preferable to phasein the transfer over a period of weeks or months to facilitate a smooth transition. oversight is being transferred because of theclosure of an IRB, the original IRBis expected to inform all clinical investigators and/or sponsors, as appropriate, of the pending closure date. If oversight by a new IRB cannot be obtained by the closure dateapproval for the research would be considered suspended or terminatedwithno further subject enrollmenthe original IRB must follow its written procedures for ensuring prompt reporting to itsinstitutional officals d FDA ofthe suspension or terminationas required under 21 CFR 56.108(b)(3).In addition, sponsors of device studies must reportto FDA and all reviewing IRBs and participating investigators anyinstances of IRBwithdrawal of approvalof an investigation or a part of an investigation within 5 working days after receipt of the withdrawal of approvalponsors of drug/biologicstudies must report to FDAthediscontinuance of clinical investigation.Conducting a view by the receiving IRB, where appropriate, before acceptresponsibility for the study(ies)Because the regulations do not address transfer of IRB oversight,it is left to e receiving IRB to decide whether to conduct a review of the clinical investigationprior to the next continuing review date established by the originalIRB.In practice, however, IRBs often choose to perform some type of review before accepting responsibility for a study, as part of their own due diligenceeffortsA number of options are available to thereceivingIRB, depending on the circumstances. The receiving IRB may decide to:Undertake an initialreview,either by the convened IRB or under an expedited review procedureif appropriate.eview by the receiving IRB is strongly recommended where the quality of the review by the original IRB may bequestionable, for examplewhere the transfer occurs because of noncompliance by the original IRB, as reflected in an FDA Warning Letter to that IRBIn addition, the receiving IRB should also consider conducting an initial review for higher risk studies, such as those involving an exception See 21 CFR 56.103.See 21 CFR 312.60, 21 CFR 312.66, 21 CFR 812.40, 21 CFR 812.42 and 21 CFR 812.64.When IRB approval of a clinical investigation is suspended or terminated, IRBsshould establish procedures to ensure that the rights and welfare of currently enrolled subjects are protected, subjects are not put at risk, and subjects receive appropriate care during any period in which the IRB and clinical investigator are attempting to resolve any remaining issues. For more information regarding suspensions or terminations of IRB approval, you may refer to FDA’s uidance, “IRB Continuing Review after Clinical Investigation Approval,” available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf . See “IRB Continuing Review after Clinical Investigation Approval,” available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf . 21 CFR 812.150(b)(2).21 CFR 312.31(a)(2).In other contexts,FDA recognizes that one IRB may rely on the review of another qualified IRB to avoid duplication of effort. See 21 CFR 56.114 (Cooperative research).For categories of research that are eligible for review through an expedited review procedure, see: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm119074.htm . ��Contains Nonbinding Recommendations 9 from the informed consent requirements under 21 CFR 50.24, unapproved therapies with a high risk of morbidity and/or mortality, novel therapies including new cellular or gene therapies, and those flagged by the original IRB for more frequent review. The receiving IRB may also decide to conduct an initial review if, for example, the IRB believes that there may be local issues that would warrant its review. Initial review should also be considered where the receiving IRB has no familiarity with the original IRB, such that it may not be comfortable wholly relying onthe original IRB’s review and approval.The IRB should consider whether to conduct an initial review of device studies to make an independent determination of significant or nonsignificant device risk, particularly when the transfer occurs because of noncompliance by the original IRB.Undertake a continuingreviewat the time of transfereither by the convened IRB or under an expedited review procedureif appropriateContinuing review may be appropriate when the receiving IRB already has responsibility for a site in a multisite study (i.e., is familiar with the study becausethe receiving IRB has already reviewed and approved the study protocol).Not undertake a review until the nextcontinuing review date.This option may be most appropriate for transfers due to logistical, administrative, or economic reasons. In practicehowever, IRBs often choose to perform some sort of informal assessment to ensure that the records appear to be in order and to help prepare for the continuing reviewwhen it comes due.Because a request for IRB approval of a protocol or informed consent change may occur even before the continuing review dateit is important to note that receiving IRBsmust perform either an initial or continuing review fore approving substantive changes to the research or the informed consent documentto ensure that they are sufficiently familiar with the studyFDA regulations at 21 CFR part 56 make no provision for a grace period extending the conduct of research beyond the expiration date of IRB approval. When the receiving IRB’sreview of the transferred research does not occur prior to the end of the approval period specified by theoriginalIRB, IRB approval expires automaticallyandall research activities involving human subjects must stop. Enrollment of new subjects cannot occur after the expiration of IRB approval.Overall, FDA expects that lapses of IRB approval will be a rare occurrence.FDA reminds receiving IRBs that theyalsothe authority to suspend or terminate approval of research in circumstanceswhere the clinical investigation is not being conducted in accordance with thereceiving IRB’s requirements or has been associated with unexpected serious harm to subjectsThe receiving IRB must promptly report asuspension or termination of IRB approval, includingthe reasonsforthe action, to the clinical investigator, 21 CFR 812.66.See 21 CFR 56.103(a), 21 CFR 56.108(a)(4), and 21 CFR 56.110(b)(2). There is an exceptionto this general requirement: changes necessary to eliminate apparent immediate hazards to human subjectsmay be initiated without IRB review and approval, as described in 21 CFR 56.108(a)(4).See, e.g.,21 CFR 56.103(a). For information regarding lapses in IRB approval and temporary continuing participation of already enrolled subjects, see FDA’s uidance, “IRB Continuing Review after Clinical Investigation Approval,” available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf . 21 CFR 56.113. ��Contains Nonbinding Recommendations 10 appropriate institutional officials, and FDA.FDA recommends that sponsors also be informedof any suspension or termination and the reasonsfor such actionInforming sponsors of an IRB suspension or termination of the study allows sponsorthe opportunity to address theIRB’sconcernsso that disruptions of the study can be minimized and any human subject protection issues can be addressedponsormust also report such informationto FDAponsors of drug/biologic studiesare required under21 CFR 312.31(a)(2) to report to FDA any information regarding the discontinuation of a clinical investigationin an information amendment to the InvestigationalNew Drug (IND) applicationponsors of device studieare required under 21 CFR 812.150(b)(2)to notify FDA and all reviewing IRBs and participating investigators of any withdrawal of IRB approval of an investigation or a part of an investigation within 5 working days after receipt of the withdrawal) Confirmingor establishingthe date for the next continuing review.If the receivingIRB performs a review at the time of clinical investigationtransfer(whether an initial or a continuingreview),it may choose to maintain the anniversary date of approval established by the original IRBor decide to establish a new anniversary date.If the receiving IRBdecides to establisha new anniversary date, the new datemust be within one year of the receivingIRB’s review.f the receiving IRB does not conduct a review of the clinical investigationat the time of transferthe date of clinical investigationapproval by the original IRBis presumed to remain in effect for the full approval period established at the time of the most recent review by the original IRBFor example, if the original IRBinitially approved the clinical investigationfor one year effective July 1, 201, and the clinical investigation is transferred to a new IRB effective October , the expiration date of IRB approval would continue to be July , unless or until the receiving IRB establishes a new expiration date. Notethatreview in accordance with a newly established expiration date wouldnonethelessneed to be conductedprior to theoriginalJuly 1, 201expiration dateDetermining whether the consent formneeds to be revisedhe informed consent document is required to contain “ “a]n explanation of whom to contact for answers to pertinent questions about the research and research subjectsrights, and whom to contact in the event of a researchrelated injury to the subject.”Therefore, when change in IRB oversight resultin changes inthe contact information regarding subject rights and/or whocontact in the event of researchrelated injury, the new contact information must be provided Ibid.For further information about reporting of suspensions or terminations of IRB approval, refer to FDA’s guidance on “IRB Continuing Review after Clinical Investigation Approval,” available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf . We note that, the device regulations place this responsibility on investigators. However, IRBs may nonetheless also choose to inform sponsors of a termination or suspension and the reasons for doing so. 21 CFR 812.150(a)(2).21 CFR 50.25(a)(7). ��Contains Nonbinding Recommendations 11 to subjects.For subjects who are already enrolled(whether or not they are active)his may be accomplished in a number of ways, including sendingletter oviding the relevant contact information.For new subjects, the informed consent, assent, and/or parental permission formmust be revised to reflect the new contact informationThe clinical investigator shouldpromptly notify the IRB of any such administrative changesto the consent form.ther changes to the consent formmay also be necessary, for example, if the receiving IRB requires modifications to the consent form at the site(s) under its jurisdictions a condition of approval (e.g., changes itemplatelanguage, changesin risks, etc.).Depending upon the types of changes needed, they may be conveyed to the clinical investigatorand sponsoras required modifications to secure IRB approval for the clinical investigation at that site or sites and may require reporting to FDA) Notifyingthekey parties.As discussed above, all key parties involved in the transfer of oversight (e.g., clinical investigator, sponsor, and originaland receiving IRBs) should discuss their respective responsibilities before implementing the transfer. In addition, the sponsor should notify pertinent entities involved in the clinical investigation e.g., institutional members, Data Safety Monitoring Board, CRO, as and when appropriate. After IRB transfer of ersight for the clinical investigation is complete, the sponsor must update the associated INDor IDEwith the name and contact information of the receving IRB and should include theeffectivedate of transferFor studies for which the original IRB acts as a central IRB, those local institutions/IRBs that have written agreements with the original IRB (to transfer review responsibility to thatoriginal IRBshould be notified that responsibility for the study isnowbeing transferred to a new central IRB (receiving IRB).We recommend that those local institutions/IRBs be given the option to enter into new written agreements with the receiving IRB or opt out of the central review arrangement if they do notlievecentral review by the receiving IRB isappropriate for their local institution (e.g., are concerned about the ability of the receivingIRB to adequately address local issuesAdditionallyhen an IRB declines to accept oversight of a clinical investigation, FDA recommends that the IRBnotify the appropriate partieswho initiated the transfer process (refer to page 3 for further information; parties responsible for initiating the transfer may not be those responsible for securing IRB reviewto enablethe clinical investigator and/or sponto make alternate arrangements forIRBreview. FDA does not require subjects who are already enrolled (whether or not they are active) to be reconsented for such minor changes; however, IRBs may choose to do so.21 CFR 50.25(a)(7).21 CFR 56.109(a) and (b).See,e.g., 21 CFR 56.109(a), 21 CFR 312.31, and 21 CFR 812.35.21 CFR 312.31(a).21 CFR 812.35(a)(4).For more information on the responsibilities of central IRBs and local institutions/IRBs with respect to central IRB review, see “Using a Centralized IRB Review Process in Multicenter Clinical Trials,” available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm . ��Contains Nonbinding Recommendations 12 Updating IRB egistration nformationThe IRB registration ruleat 21 CFR 56.106(e)requires thatany IRB that decides toreview FDAregulated research involving newtypeof FDAregulated producor decides discontinue reviewing FDAregulated researchmustrevise its registration within 30 days of the change in product type review or permanent cessation of the IRB’s review of research. receiving IRB may therefore need to revise its registration if it previously did not reviewclinical investigations FDAregulated products orif itwill assume the review for a new type of FDAregulated product upon the acceptance of clinical investigations from aoriginal IRB(e.g.thereceivingIRB will now review clinical investigations of medical deviceswhereas the IRB previously reviewed only clinical investigations of drug). Similarly, the original IRBmay need to update its registration information if it will no longer be reviewing a certaintype of FDAregulated product, will no longer be reviewing FDAregulated research, or plans to disbandIRBs must revise their registration within 30 days of any suchchangeand may do so electronically through http://ohrp.cit.nih.gov/efile IV.SPECIAL SITUATIONS A. Transfer of IRB Oversight from one IRB to Another IRBwithin the Same Institution and Temporary Transfer of IRB Review ResponsibilityTransfer of oversight may occur from one IRB to another IRBthat operatewithinthe same institutionfor logistical, administrativeand/or budgeting reasons e.g.consolidating IRB workloadTransfer of oversight might also occur temporarily when natural disaster or other disruptive event briefly suspendsthe functioning of the original IRB; in this case, the transfer is only temporarybecause responsibility for IRB review will eventually revert back to the original IRB. When the transfer occurs within the same institution(e.g., for logistical, budgeting or administrative reasons)the transfer processis generally expectedto bsimpler and more expeditiousthan the transferdescribed above in Section IIIas not all eight steps may be applicable.For example, when oversight is transferred to another IRB at the same institution, the receiving IRB may decide not to conduct an initial or continuing review prior to the next continuing review date established by the original IRB, as such review may not be expected to substantively add to human subject protection.The guidance provided in Section III for institutioninstitution transfers may be useful for withininstitution transfers. When atemporary transfer of IRB oversightoccurs (e.g., due to a natural disaster)whetherwithin the same institution or to a different institution,the guidance provided in Section III should be useful, but again, not all eightsteps may apply. The appropriate steps to effectuate oversight transfer will depend on the specific circumstances, including IRBs thatlack the ability to access the electronic registration systemmaysend revisions, in writing, to the Office of Good Clinical Practice, Office of Special Medical Programs, Food and Drug Administration, 10903 New Hampshire Avenue, WO325103,Silver Spring, MD 20993 ��Contains Nonbinding Recommendations 13 the reasons for the transferand the risk posed by the study. In the case of a natural disaster, although the transfer may initially be thought to only be required for a short period of time, additional time may ultimately be needed before the original IRB is able to resume its oversight responsibilities. The original and receiving IRBs would need to ensure that study oversight does not lapse;adverse events are reported to the appropriate IRB, etc. during this interim period. Transfer of a Clinical Investigation to a New Research Site Requiring IRB Review sponsor may decideto transfer a clinical investigation to a different research sitewhenfor instance,a clinical investigator relocates to that new siteBecause the transfer involves changes to theresearch (i.e., conducting the research in a new location, consent form revisions, possible changes in key staff, etc.), the sponsor or investigator must submit these changesto the receiving IRB for review and approval, prior to implementing the changesIn many cases, these changes represent a “minor change” to the researchwhichthe IRB may review under an expedited review procedure.ch a move to a newresearch site may or may not entail changing the IRBIf thereviewing IRB changeas a resul, then the considerations described in ection III applyexcepinitial or continuing IRB reviewmust be conductedn IRB may not approve a change in research without first conducting an initial or continuing reviewFDA notes that, even the B remainthe samewhen a study is transferred to a new research site, IRB reviewapproval for the new research site isrequiredbecause such a move is considered a change in previously approved researchAdditionally, the sponsor mustnotify FDA of changein research site, clinical investigator, and/or IRBFor drug or biologics studies, thisnotificationcan generally be accomplished through anIND protocol or information amendment, whereasfor device studiesit can generally be accomplished in IDE annual reportV. ADDITIONAL QUESTIONSABOUT TRANSFERRINGOVERSIGHT OF CLINICAL INVESTIGATIOccasionally, during the course of its initialor continuingreview of transferred clinical investigationor at other times during oversight transfern originalor receiving IRB may have 21 CFR 56.108(a)(4). For drug/biologic studies, clinical investigators are responsible for securing IRB approval under 21 CFR 312.66; for device studies, the sponsor is responsible under 21 CFR 812.35(a)(1) and (3).21 CFR 56.110(b)(2)See 21 CFR 56.103(a), 21 CFR 56.108(a)(4), and 21 CFR 56.110(b)(2). There is an exceptionto this general requirement: changes necessary to eliminate apparent immediate hazards to human subjectsmay be initiated without IRB review and approval, as described in 21 CFR 56.108(a)(4).Ibid.See 21 CFR 312.30, 21 CFR 312.31, 21 CFR 812.35, and 21 CFR 812.150(b)(5). For a discussion of the types of anges in an IND studythatrequire a new Form 1572, refer toQuestion 7 of FDA’s Guidance Frequently Asked Questions Statement of Investigator (Form FDA 1572),”available at http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm214282.pdf ��Contains Nonbinding Recommendations 14 questionsthat are not resolvable through communications with the sponsor or clinical investigator. In such situations, eitherIRB may contact FDA for additional guidance. Affected ponsors and clinical investigators may alsocontact FDA in these situationslease use the followingas an initial point of contactCenter for Biologics Evaluation and Research (CBER) Bioresearch Monitoring Branch, Division of Inspections and Surveillance, Office of Compliance and Biologics QualityPhone: (301) 827Email: industry.biologics@fda.gov Center for Drug Evaluation and Research (CDER) Officeof Scientific Investigations, Office of CompliancePhone: (301) 796Email: cderosi@fda.hhs.gov Center for Devices and Radiological Health (CDRH) Division of Bioresearch Monitoring, Office of CompliancePhone: (301) 796Email: bimo@cdrh.fda.gov If you have specific questions about how to interpretthis guidance, please contactFDAphone 01) 796or by email at gcp.questions@fda.hhs.gov .