August 1, 2011 | Volume 1, Issue 2

The Quorum Review: Institutional Edition

Letter from the CEO Each month seems to bring new changes to the landscape of the research community. This month, our newsletter summarizes newly released revisions to the federal-wide assurance (FWA) documents and requirements. This newsletter also includes an article that summarizes upcoming changes in FDA’s safety reporting requirements. In future newsletters, we will address the recently released OHRP Guidance on Written IRB Procedures and the Updated 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 the requirements for clinical trials. One of the keys to maintaining an effective, independent ethics board is to stay abreast of current issues in bioethics and to establish a complete and well-rounded understanding of the regulations. Our IRB members attend monthly in-services and an annual offsite meeting. We provide journal resources to our IRB members and we frequently host webinars for our staff and members. We support the Certified IRB Professional program – I am proud to report that 60% of our in-house IRB members, 40% of our regulatory 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 to the CITI on-line IRB training. Our attorneys recently prepared a free webinar on the regulatory parameters for using social media for recruitment – you can access the webinar here. Our quarterly newsletters also summarize recent regulatory changes. For a complete set of back issues, please go to this page. Please let us know if you would like 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 your organization. Please feel free to let us know how we can assist you in meeting your research goals.

Sincerely,

Cami Cami Gearhart, CEO

Quorum Review IRB

August 1, 2011 | Volume 1, Issue 2

Adding Quorum Review IRB to an Institution’s FWA Quorum often receives questions about FWAs and adding us as an IRB of Record. The following information is provided to answer these questions as well as to provide general information on what an FWA is, who needs one, and when and how to add Quorum as an IRB of Record. We’ll also summarize the recent updates to the FWA guidance released earlier this summer.

Federal Regulation 45 CFR 46.103 requires those institutions that become engaged in research conducted or supported by a federal agency or department that has adopted the Common Rule to provide written assurance. This is accomplished by submitting a Federalwide Assurance (FWA). For the purposes of the FWA, federally-supported means the U.S. Government providing any funding or other support.1 Generally, if an institution is submitting a research study to an IRB, then likely the institution is “engaged in research. Additionally, the institution must designate one or more IRBs on their FWA.

Recent revisions to the Terms of Federalwide Assurance for the Protection of Human Subjects have changed how an institution designates an IRB of Record on the FWA. If an institution has an FWA and is submitting research covered by the terms of the FWA to Quorum Review IRB (Quorum), the institution may need to designate Quorum on its FWA as an IRB of Record if the

1 Federalwide Assurance for the Protection of Human Subjects, Terms of the Federalwide Assurance (FWA) for Institutions, Section 2 - Applicability

institution has not already designated an internal IRB(s) or has already designated an external IRB that reviews the largest percentage of research to which the FWA applies.2 Even if an institution does not designate Quorum as an IRB of Record on their FWA, the institution still must execute a written agreement with Quorum documenting the relationship and responsibilities.

To designate Quorum as an IRB of Record on the FWA, simply include “Quorum Review IRB” and Quorum’s IRB registration number IRB00003226 on the FWA. The written agreement can be an IRB Authorization Agreement (either study-specific or an Umbrella agreement), a Joint Oversight Agreement, or a Master Jurisdiction Agreement. To complete an IRB Authorization Agreement with Quorum, simply complete the document located on Quorum’s website and submit with your submission to Quorum.

If there are any questions on how to complete an FWA, please see the Department of Health and Human Services Regulations Guidance titled, “Step-by-Step Instructions for Filing a Federalwide Assurance.”3 Otherwise, Quorum is always available to answer questions.

2 Federalwide Assurance Instructions, Step-by-Step Instructions for Filing a Federalwide Assurance, Item #6 3 http://www.hhs.gov/ohrp/assurances/forms/fwainstructions.html

August 1, 2011 | Volume 1, Issue 2

Regulatory Recap: FDA Issues Final Rule Regarding Safety Reporting Requirements for IND and Bioavailability / Bioequivalence Studies Safety reporting is critical to protecting the safety and welfare of research subjects in clinical trials and is important in developing accurate data on investigational drugs. Due to the undoubted importance of safety reporting, the Food and Drug Administration (FDA) has issued a final rule on safety reporting requirements that is intended to clarify such requirements. While the rule is for sponsors and investigators, the rule also directly pertains to Institutional Review Boards (IRB) that review clinical trials involving investigational drugs. Below is a summary of the rule providing information on the key changes and new requirements. On September 28, 2010, the Food and Drug Administration (FDA) issued a final rule entitled “Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans.”4 The rule, which goes into effect on March 28, 2011, amends the FDA’s regulations regarding the safety reporting requirements for studies conducted under an investigational new drug application (IND) found at 21 CFR part 312 and 4 75 Fed. Reg. 59935 (Sept. 29, 2010). Available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf.

bioequivalence and bioavailability studies conducted to support the approval of generic drugs found at 21 CFR part 320.5 Additional detail regarding the final rule is outlined in the FDA’s concurrent draft guidance entitled “Safety Reporting Requirements for INDs and BA/BE Studies,”6 a FDA News Release,7 and a FDA Q&A document.8

The intent of the changes to the safety reporting requirements is to “improve the overall quality of safety reporting, strengthen FDA’s ability to review critical safety information, improve safety monitoring of human drug and biological products, and harmonize safety reporting internationally.”9

Under the current regulations, sponsors are required to notify the FDA and investigators, in an IND Safety Report, of any adverse experience “associated with the use of the drug that are both serious and

5 Effective Date of Rule is 03/28/2011. However, per 03/25/2011 FDA Notice, “FDA strongly encourages compliance with the new regulations as soon as possible, and [] expect[s] all sponsors to be in compliance with the new regulations no later than September 28, 2011.” http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm248650.htm. 6 FDA Guidance for Industry (Sept. 2010). Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf. 7 FDA News Release; FDA issues rule on safety information during a clinical trial. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227386.htm. 8 Q & A: Final Rule - New Safety Reporting Requirements for Investigational New Drug Applications (INDs). Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm226365.htm. 9 Id. at 1.

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unexpected and any finding from tests in laboratory animals that suggest a risk to human subjects.”10 The language “associated with the use of the drug” is defined to mean that ‘there is a reasonable possibility that the experience may have been caused by the drug.11 Sponsors often interpret this to mean that they are required to report serious adverse experiences as individual events even though it is unlikely that the event was caused by the drug. The draft guidance refers to the following examples of events that have been reported by sponsors to illustrate this point:

Serious adverse experiences (e.g., mortality or major morbidity) that are likely to have been manifestations of the underlying disease.

Serious adverse experiences that commonly occurred in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population).

Serious adverse experiences that were study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events).12

According to the FDA, these types of events do not meet the definition of “associated with the use of the drug” and should not be reported in an IND Safety Report. The guidance also emphasizes the “drain on resources” when the FDA, investigators, and institutional review boards are inundated with “generally uninformative” IND Safety Reports especially when reported as single events without any

10 Id. at 2. 11 Id. at 2. 12 Id. at 2.

context.13 The new regulations are therefore intended to address these concerns by clarifying the safety reporting requirements and articulating when it is sufficient to submit an IND Safety Report for a single event and when events should be submitted in the aggregate.14

Summary of the Final Rule

There are a number of clarifications, modifications, and new requirements in the final rule including the following:

1. Changes to definitions and clarifications regarding the requirement to report any suspected adverse reactions that are both serious and unexpected

In order to clarify the types of serious adverse events that should be reported to the FDA and investigators, the definition for the phrase “associated with the use of the drug” is being replaced with new definitions.15 For example, the new regulations will eliminate the “adverse drug experience” definition and replace it with two phrases “adverse event” and “suspected adverse reaction.”16 A summary of the key definitions is below. Additional information is contained in the FDA’s draft guidance.17

13 Id at 2. 14 Id at 2-3. 15 Id. at 3. 16 Id. at 3-6. 17 Id.

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Term/Phrase Definition Under the New Rule

Adverse Event

Means any untoward medical occurrence associated with the use of the drug in humans, whether or not considered drug related.18

Adverse Reaction

Means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions for which there is a reason to conclude that the drug caused the event.19

Suspected Adverse Reaction

Means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For purposes of IND safety reporting. “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by the drug.20

Unexpected An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

"Unexpected," …also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.21

18 Revised 21 CFR 312.32(a). 19 FDA Guidance for Industry (Sept. 2010) at 4. 20 Id. at 4; Revised 21 CFR 312.32(a). 21 Id. at 5; Revised 21 CFR 312.32(a).

The FDA emphasizes, that before submitting an IND Safety Report, the sponsor must ensure that the adverse event meets all three of the definitions contained in the requirements: (1) Suspected Adverse Reaction; (2) Serious; and (3) Unexpected. An IND Safety Report should not be submitted if it does not meet all three required elements. Further, the FDA noted that in order to avoid submitting uninformative IND Safety Reports, it is essential for the sponsor to carefully evaluate whether or not the event meets the suspected adverse reaction definition – that there is a “reasonable possibility that the drug caused the adverse event.” If the adverse event does not meet this definition, it should not be reported to the FDA.

The new requirements also provide the following three examples for when the sponsor must report, in an IND Safety Report, a suspected adverse reaction that is both serious and unexpected: (1) Individual Occurrences22 (“A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome).”); (2) One or more Occurrences23 (“One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 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 condition

22 Revised 21 CFR 312.32(c)(1)(i)(A). 23 Revised 21 CFR 312.32(c)(1)(i)(B). 24 Revised 21 CFR 312.32(c)(1)(i)(C).

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under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.”). These examples are discussed in detail in the FDA draft guidance.25

2. New and Modified Requirement Regarding Findings from Other Sources

The revised regulations include a new requirement to report findings from “other studies” that “suggest a significant risk in humans exposed to the drug.”26 The phrase “other studies” includes “ongoing or completed clinical studies, polled data from multiple studies, epidemiological studies, and published and unpublished scientific papers.”27 The revised regulations also include a modified requirement for sponsors to submit IND Safety Reports for in vitro testing and clarification regarding the types of findings from animal testing that must be reported.28 Under the current regulations, an IND Safety Report is only required for any findings from animal testing which suggest a significant risk in humans. The final rule therefore expands the reporting requirements. The new and modified requirements require the sponsor to promptly report findings for studies from any source regardless of whether or not they are “conducted under the IND or by the sponsor.”29 As noted by the FDA, such findings typically require

25 FDA Guidance for Industry (Sept. 2010) at 6-9. 26 Revised 21 CFR 312.32(c)(1)(ii). 27 FDA Guidance for Industry (Sept. 2010) at 11. 28 Revised CFR 312.32(c)(1)(iii). 29 FDA Guidance for Industry (Sept. 2010) at 11.

changes to the protocol, informed consent document, investigator brochure, “or other aspects of the overall conduct of the clinical investigation.”30

3. New Requirement to Report Increased Rate of Occurrence of Serious Expected Adverse Reactions

The rule includes a new requirement that the “sponsor must report any clinically important increase in the rate of the serious suspected adverse reaction over that listed in the protocol or investigator brochure.”31 In determining whether or not to report, the sponsor may consider a number of factors “including the study population, the nature and seriousness of the reaction, and the magnitude of the observed increase in the rate.”32

4. Submission of IND Safety Reports / Reporting Format or Frequency

The submission timelines for submitting an IND Safety Report remain unchanged, but do include a requirement that the sponsor submit to the FDA “any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request.”33

5. Investigations of Marketed Drugs The final rule clarifies that sponsors must submit IND Safety Reports for a drug marketed or approved in the United States under an IND for “suspected adverse reactions observed in a clinical study” but 30 Id. 31 Revised 21CFR 312.32(c)(1)(iv). 32 FDA Guidance for Industry (Sept. 2010) at 12; Revised 21 CFR 312.32(c)(1)(iv). 33 21 CFR 312.32(c)(1)(v).

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that they must also adhere to applicable postmarketing safety reporting requirements.34

6. Reporting Study End Points A requirement has been added to the final rule which states that “if a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between the drug and the event (e.g. death from anaphylaxis), the event must be reported … as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint.”35

7. Investigator Reports According to the new reporting requirements, all serious adverse events must be reported to the sponsor even if they are not related to the drug or expected. In addition, Investigators are required to “include an assessment of whether there is reasonable possibility that the drug caused the events.”36

8. Bioavailability and Bioequivalence Requirements

The final rule includes a new requirement that requires a person conducting a Bioavailability or Bioequivalence study to notify all investigators and the FDA about “any serious adverse event, whether or not the event is considered drug related” as soon as possible, “but in no case later than 15 days after becoming aware of its occurrence.”37

34 Revised 21 CFR 312.32(c)(4); See 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 21 CFR 312.64(b). 37 FDA Guidance for Industry (Sept. 2010) at 18.

Implications of the Revised Safety Reporting Requirements

With the emphasis being placed on whether or not there is evidence to suggest a causal relationship between the adverse event and the drug and the fact that the new requirements make clear the circumstances for when it is appropriate to submit an individual occurrence, one or more occurrences, or an aggregate analysis, the FDA believes that the final rule will reduce the number of uninformative IND Safety Reports that are being submitted. As noted in the draft guidance, “[t]hese clarifications should increase the likelihood that submitted information will be interpretable and will meaningfully contribute to the developing safety profile of the investigational drug and improve the overall quality of safety reporting.” The new requirements also should improve the quality and reduce the number of redundant reports submitted to the IRB.38

This is not to say however, that challenges will not exist. Sponsors and investigators will likely have to make changes to their policies and procedures in order to comply with the new requirements. In addition, IRB’s will have to evaluate their own requirements and expectations regarding the safety reports received from investigators (and sponsors who submit on an investigator’s behalf). The FDA acknowledges that revisions to the current investigator reporting requirements to IRBs may be necessary in order to address any issues that arise.39

38 Id. at 3, 7-9. 39 75 Fed. Reg. 59935, 59995 (Sept. 29, 2010).

August 1, 2011 | Volume 1, Issue 2

A Warm Welcome Quorum extends a warm welcome to the 15 research organizations, academic medical centers, hospitals, and universities 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