Institution Newsletter Volume1, Issue 2

August 1, 2011 | Volume 1, Issue 2The Quorum Review: Institutional EditionLetter from the CEOEach month seems to bring new changes to the landscape of the research community. This month, our newslettersummarizes newly released revisions to the federal-wide assurance (FWA) documents and requirements. Thisnewsletter also includes an article that summarizes upcoming changes in FDA’s safety reporting requirements. Infuture newsletters, we will address the recently released OHRP Guidance on Written IRB Procedures and theUpdated Guidance on Reporting Incidents to OHRP.Here at Quorum Review, we believe it is critical for our IRB members, staff and clients to stay up-to-date on therequirements for clinical trials. One of the keys to maintaining an effective, independent ethics board is to stayabreast of current issues in bioethics and to establish a complete and well-rounded understanding of theregulations. Our IRB members attend monthly in-services and an annual offsite meeting. We provide journalresources to our IRB members and we frequently host webinars for our staff and members. We support theCertified IRB Professional program – I am proud to report that 60% of our in-house IRB members, 40% of ourregulatory staff and 20% of our study management and study support positions have earned their CIP.For you, our clients, we provide a range of educational resources. Clients of Quorum Review have free access tothe CITI on-line IRB training. Our attorneys recently prepared a free webinar on the regulatory parameters forusing social media for recruitment – you can access the webinar here. Our quarterly newsletters also summarizerecent regulatory changes. For a complete set of back issues, please go to this page. Please let us know if you wouldlike any additional support for your IRB or investigators as we all try to navigate this dynamic field.We are pleased to have you receive this newsletter and believe the information provided will be helpful to yourorganization. Please feel free to let us know how we can assist you in meeting your research goals.Sincerely,CamiCami Gearhart, CEOQuorum Review IRB

August 1, 2011 | Volume 1, Issue 2Adding Quorum Review IRB institution has not already designated an internal IRB(s) or has already designated an external IRB thatto an Institution’s FWA reviews the largest percentage of research to whichQuorum often receives questions about FWAs and the FWA applies.2 Even if an institution does notadding us as an IRB of Record. The following designate Quorum as an IRB of Record on theirinformation is provided to answer these questions as FWA, the institution still must execute a writtenwell as to provide general information on what an agreement with Quorum documenting theFWA is, who needs one, and when and how to add relationship and responsibilities.Quorum as an IRB of Record. We’ll also summarize To designate Quorum as an IRB of Record on thethe recent updates to the FWA guidance released FWA, simply include “Quorum Review IRB” andearlier this summer. Quorum’s IRB registration number IRB00003226Federal Regulation 45 CFR 46.103 requires those on the FWA. The written agreement can be an IRBinstitutions that become engaged in research Authorization Agreement (either study-specific or anconducted or supported by a federal agency or Umbrella agreement), a Joint Oversight Agreement,department that has adopted the Common Rule to or a Master Jurisdiction Agreement. To complete anprovide written assurance. This is accomplished by IRB Authorization Agreement with Quorum, simplysubmitting a Federalwide Assurance (FWA). For the complete the document located on Quorum’spurposes of the FWA, federally-supported means the website and submit with your submission toU.S. Government providing any funding or other Quorum.support.1 Generally, if an institution is submitting a If there are any questions on how to complete anresearch study to an IRB, then likely the institution FWA, please see the Department of Health andis “engaged in research. Additionally, the institution Human Services Regulations Guidance titled, “Step-must designate one or more IRBs on their FWA. by-Step Instructions for Filing a FederalwideRecent revisions to the Terms of Federalwide Assurance.”3 Otherwise, Quorum is always availableAssurance for the Protection of Human Subjects to answer questions.have changed how an institution designates an IRBof Record on the FWA. If an institution has anFWA and is submitting research covered by theterms of the FWA to Quorum Review IRB(Quorum), the institution may need to designateQuorum on its FWA as an IRB of Record if the 21 Federalwide Assurance for the Protection of Human Subjects, Federalwide Assurance Instructions, Step-by-Step InstructionsTerms of the Federalwide Assurance (FWA) for Institutions, for Filing a Federalwide Assurance, Item #6 3Section 2 - Applicability http://www.hhs.gov/ohrp/assurances/forms/fwainstructions.html

August 1, 2011 | Volume 1, Issue 2Regulatory Recap: bioequivalence and bioavailability studies conducted to support the approval of generic drugs found at 21FDA Issues Final Rule Regarding CFR part 320.5 Additional detail regarding the finalSafety Reporting Requirements rule is outlined in the FDA’s concurrent draft guidance entitled “Safety Reporting Requirementsfor IND and Bioavailability / for INDs and BA/BE Studies,”6 a FDA NewsBioequivalence Studies Release,7 and a FDA Q&A document.8Safety reporting is critical to protecting the safety and The intent of the changes to the safety reportingwelfare of research subjects in clinical trials and is requirements is to “improve the overall quality ofimportant in developing accurate data on safety reporting, strengthen FDA’s ability to reviewinvestigational drugs. Due to the undoubted critical safety information, improve safetyimportance of safety reporting, the Food and Drug monitoring of human drug and biological products,Administration (FDA) has issued a final rule on and harmonize safety reporting internationally.”9safety reporting requirements that is intended to Under the current regulations, sponsors are requiredclarify such requirements. While the rule is for to notify the FDA and investigators, in an INDsponsors and investigators, the rule also directly Safety Report, of any adverse experience “associatedpertains to Institutional Review Boards (IRB) that with the use of the drug that are both serious andreview clinical trials involving investigational drugs.Below is a summary of the rule providing 5information on the key changes and new Effective Date of Rule is 03/28/2011. However, per 03/25/2011 FDA Notice, “FDA strongly encourages compliance with the newrequirements. regulations as soon as possible, and [] expect[s] all sponsors to be inOn September 28, 2010, the Food and Drug compliance with the new regulations no later than September 28,Administration (FDA) issued a final rule entitled 2011.” http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugs“Investigational New Drug Safety Reporting areDevelopedandApproved/ApprovalApplications/InvestigationalNewRequirements for Human Drug and Biological DrugINDApplication/ucm248650.htm.Products and Safety Reporting Requirements for 6 FDA Guidance for Industry (Sept. 2010). Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatBioavailability and Bioequivalence Studies in oryInformation/Guidances/UCM227351.pdf.Humans.”4 The rule, which goes into effect on 7 FDA News Release; FDA issues rule on safety information during aMarch 28, 2011, amends the FDA’s regulations clinical trial. Available atregarding the safety reporting requirements for http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/u cm227386.htm.studies conducted under an investigational new drug 8 Q & A: Final Rule - New Safety Reporting Requirements forapplication (IND) found at 21 CFR part 312 and Investigational New Drug Applications (INDs). Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugs4 75 Fed. Reg. 59935 (Sept. 29, 2010). Available at areDevelopedandApproved/ApprovalApplications/InvestigationalNewhttp://frwebgate.access.gpo.gov/cgi- DrugINDApplication/ucm226365.htm. 9bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf. Id. at 1.

August 1, 2011 | Volume 1, Issue 2unexpected and any finding from tests in laboratory context.13 The new regulations are thereforeanimals that suggest a risk to human subjects.”10 The intended to address these concerns by clarifying thelanguage “associated with the use of the drug” is safety reporting requirements and articulating whendefined to mean that ‘there is a reasonable possibility it is sufficient to submit an IND Safety Report for athat the experience may have been caused by the single event and when events should be submitted indrug.11 Sponsors often interpret this to mean that the aggregate.14they are required to report serious adverseexperiences as individual events even though it is Summary of the Final Ruleunlikely that the event was caused by the drug. The There are a number of clarifications, modifications,draft guidance refers to the following examples of and new requirements in the final rule including theevents that have been reported by sponsors to following:illustrate this point: 1. Changes to definitions and clarifications Serious adverse experiences (e.g., mortality or regarding the requirement to report any major morbidity) that are likely to have been suspected adverse reactions that are both manifestations of the underlying disease. serious and unexpected Serious adverse experiences that commonly In order to clarify the types of serious adverse occurred in the study population independent of events that should be reported to the FDA and drug exposure (e.g., strokes or acute myocardial investigators, the definition for the phrase infarctions in an elderly population). “associated with the use of the drug” is being replaced with new definitions.15 For example, the Serious adverse experiences that were study new regulations will eliminate the “adverse drug endpoints (i.e., the study was evaluating whether experience” definition and replace it with two the drug reduced the rate of these events).12 phrases “adverse event” and “suspected adverseAccording to the FDA, these types of events do not reaction.”16 A summary of the key definitions ismeet the definition of “associated with the use of the below. Additional information is contained in thedrug” and should not be reported in an IND Safety FDA’s draft guidance.17Report. The guidance also emphasizes the “drain onresources” when the FDA, investigators, andinstitutional review boards are inundated with“generally uninformative” IND Safety Reportsespecially when reported as single events without any 13 Id at 2. 14 Id at 2-3.10 15 Id. at 2. Id. at 3.11 16 Id. at 2. Id. at 3-6.12 17 Id. at 2. Id.

August 1, 2011 | Volume 1, Issue 2Term/Phrase Definition Under the New Rule The FDA emphasizes, that before submitting an IND Safety Report, the sponsor must ensure that theAdverse Means any untoward medical occurrence associated adverse event meets all three of the definitions with the use of the drug in humans, whether or not contained in the requirements: (1) SuspectedEvent considered drug related.18 Adverse Reaction; (2) Serious; and (3) Unexpected. Means any adverse event caused by a drug. Adverse An IND Safety Report should not be submitted if itAdverseReaction reactions are a subset of all suspected adverse does not meet all three required elements. Further, reactions for which there is a reason to conclude that the drug caused the event.19 the FDA noted that in order to avoid submitting uninformative IND Safety Reports, it is essential forSuspected Means any adverse event for which there is a the sponsor to carefully evaluate whether or not the reasonable possibility that the drug caused the event meets the suspected adverse reaction definitionAdverse adverse event. For purposes of IND safetyReaction reporting. “reasonable possibility” means there is – that there is a “reasonable possibility that the drug evidence to suggest a causal relationship between caused the adverse event.” If the adverse event does the drug and the adverse event. A suspected adverse not meet this definition, it should not be reported to reaction implies a lesser degree of certainty about causality than adverse reaction, which means any the FDA. adverse event caused by the drug.20 The new requirements also provide the following An adverse event or suspected adverse reaction is three examples for when the sponsor must report, inUnexpected considered “unexpected” if it is not listed in the an IND Safety Report, a suspected adverse reaction investigator brochure or is not listed at the specificity or severity that has been observed; or, if that is both serious and unexpected: (1) Individual an investigator brochure is not required or Occurrences22 (“A single occurrence of an event that available, is not consistent with the risk is uncommon and known to be strongly associated information described in the general investigational plan or elsewhere in the current application. with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome).”); (2) One or more "Unexpected," …also refers to adverse events or suspected adverse reactions that are mentioned in Occurrences23 (“One or more occurrences of an the investigator brochure as occurring with a class event that is not commonly associated with drug of drugs or as anticipated from the pharmacological exposure, but is otherwise uncommon in the properties of the drug, but are not specifically mentioned as occurring with the particular drug population exposed to the drug (e.g., tendon under investigation.21 rupture).”); and (3) Aggregate Analysis of Specific Events24 (“An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition18 Revised 21 CFR 312.32(a).19 22 FDA Guidance for Industry (Sept. 2010) at 4. Revised 21 CFR 312.32(c)(1)(i)(A).20 23 Id. at 4; Revised 21 CFR 312.32(a). Revised 21 CFR 312.32(c)(1)(i)(B).21 24 Id. at 5; Revised 21 CFR 312.32(a). Revised 21 CFR 312.32(c)(1)(i)(C).

August 1, 2011 | Volume 1, Issue 2under investigation or other events that commonly changes to the protocol, informed consentoccur in the study population independent of drug document, investigator brochure, “or other aspectstherapy) that indicates those events occur more of the overall conduct of the clinical investigation.”30frequently in the drug treatment group than in a 3. New Requirement to Report Increasedconcurrent or historical control group.”). These Rate of Occurrence of Serious Expectedexamples are discussed in detail in the FDA draft Adverse Reactionsguidance.25 The rule includes a new requirement that the2. New and Modified Requirement Regarding “sponsor must report any clinically important Findings from Other Sources increase in the rate of the serious suspected adverseThe revised regulations include a new requirement reaction over that listed in the protocol orto report findings from “other studies” that “suggest investigator brochure.”31 In determining whether ora significant risk in humans exposed to the drug.”26 not to report, the sponsor may consider a number ofThe phrase “other studies” includes “ongoing or factors “including the study population, the naturecompleted clinical studies, polled data from multiple and seriousness of the reaction, and the magnitudestudies, epidemiological studies, and published and of the observed increase in the rate.”32unpublished scientific papers.”27 The revised 4. Submission of IND Safety Reports /regulations also include a modified requirement for Reporting Format or Frequencysponsors to submit IND Safety Reports for in vitro The submission timelines for submitting an INDtesting and clarification regarding the types of Safety Report remain unchanged, but do include afindings from animal testing that must be reported.28 requirement that the sponsor submit to the FDAUnder the current regulations, an IND Safety Report “any additional data or information that the agencyis only required for any findings from animal testing deems necessary, as soon as possible, but in no casewhich suggest a significant risk in humans. The final later than 15 calendar days after receiving therule therefore expands the reporting requirements. request.”33The new and modified requirements require thesponsor to promptly report findings for studies from 5. Investigations of Marketed Drugsany source regardless of whether or not they are The final rule clarifies that sponsors must submit“conducted under the IND or by the sponsor.”29 As IND Safety Reports for a drug marketed or approvednoted by the FDA, such findings typically require in the United States under an IND for “suspected adverse reactions observed in a clinical study” but25 FDA Guidance for Industry (Sept. 2010) at 6-9. 30 Id.26 Revised 21 CFR 312.32(c)(1)(ii). 31 Revised 21CFR 312.32(c)(1)(iv).27 FDA Guidance for Industry (Sept. 2010) at 11. 32 FDA Guidance for Industry (Sept. 2010) at 12;28 Revised CFR 312.32(c)(1)(iii). Revised 21 CFR 312.32(c)(1)(iv).29 33 FDA Guidance for Industry (Sept. 2010) at 11. 21 CFR 312.32(c)(1)(v).

August 1, 2011 | Volume 1, Issue 2that they must also adhere to applicable Implications of the Revisedpostmarketing safety reporting requirements.34 Safety Reporting Requirements6. Reporting Study End Points With the emphasis being placed on whether or notA requirement has been added to the final rule there is evidence to suggest a causal relationshipwhich states that “if a serious and unexpected between the adverse event and the drug and the factadverse event occurs for which there is evidence that the new requirements make clear thesuggesting a causal relationship between the drug circumstances for when it is appropriate to submitand the event (e.g. death from anaphylaxis), the an individual occurrence, one or more occurrences,event must be reported … as a serious and or an aggregate analysis, the FDA believes that theunexpected suspected adverse reaction even if it is a final rule will reduce the number of uninformativecomponent of the study endpoint.”35 IND Safety Reports that are being submitted. As noted in the draft guidance, “[t]hese clarifications7. Investigator Reports should increase the likelihood that submittedAccording to the new reporting requirements, all information will be interpretable and willserious adverse events must be reported to the meaningfully contribute to the developing safetysponsor even if they are not related to the drug or profile of the investigational drug and improve theexpected. In addition, Investigators are required to overall quality of safety reporting.” The new“include an assessment of whether there is requirements also should improve the quality andreasonable possibility that the drug caused the reduce the number of redundant reports submittedevents.”36 to the IRB.388. Bioavailability and This is not to say however, that challenges will not Bioequivalence Requirements exist. Sponsors and investigators will likely have toThe final rule includes a new requirement that make changes to their policies and procedures inrequires a person conducting a Bioavailability or order to comply with the new requirements. InBioequivalence study to notify all investigators and addition, IRB’s will have to evaluate their ownthe FDA about “any serious adverse event, whether requirements and expectations regarding the safetyor not the event is considered drug related” as soon reports received from investigators (and sponsorsas possible, “but in no case later than 15 days after who submit on an investigator’s behalf). The FDAbecoming aware of its occurrence.”37 acknowledges that revisions to the current investigator reporting requirements to IRBs may be34 Revised 21 CFR 312.32(c)(4); necessary in order to address any issues that arise.39See also, 21 CFR 310.305, 21 CFR 314.80, and 21 CFR 600.80.35 Revised 21 CFR 312.32(c)(5);See also, FDA Guidance for Industry (Sept. 2010) at 9-11.36 38 21 CFR 312.64(b). Id. at 3, 7-9.37 39 FDA Guidance for Industry (Sept. 2010) at 18. 75 Fed. Reg. 59935, 59995 (Sept. 29, 2010).

August 1, 2011 | Volume 1, Issue 2A Warm WelcomeQuorum extends a warm welcome to the 15 research organizations, academic medical centers, hospitals, anduniversities that added Quorum to their Federal Wide Assurances in the second quarter of 2011: Cardiovascular Research of Knoxville, Knoxville, TN Novella Clinical, Durham, NC Virginia Eye Consultants, Norfolk, VA Analab Clinical Research, Inc., Lenexa, KS Sentara Virginia Beach General Hospital, Virginia Beach, VA Good Samaritan Medical Center, West Palm Beach, FL Suburban Lung Associates, SC, Elk Grove Village, IL Omeros Corporation, Seattle, WA University of Hawaii, Honolulu, HI St. Louis University Hospital: Tenet HealthSystem SL, Inc. (dba SLUH), St. Louis, MO Providence Hospital and Medical Centers, Southfield, MI Scripps Health, La Jolla, CA Alexian Brothers Hospital Network, Arlington Heights, IL Vince & Associates Clinical Research, Overland Park, KS Center for Clinical Research, Winston-Salem, NC

Institution Newsletter Volume1, Issue 2

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