The Institutional newsletter is intended to help institutional clients feel prepared to deal with the day-to-day challenges of research ethics.

1. 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

2. August 1, 2011 | Volume 1, Issue 2
Adding Quorum Review IRB institution has not already designated an internal
IRB(s) or has already designated an external IRB that
to an Institution’s FWA reviews the largest percentage of research to which
Quorum often receives questions about FWAs and the FWA applies.2 Even if an institution does not
adding us as an IRB of Record. The following designate Quorum as an IRB of Record on their
information is provided to answer these questions as FWA, the institution still must execute a written
well as to provide general information on what an agreement with Quorum documenting the
FWA 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 the
the recent updates to the FWA guidance released FWA, simply include “Quorum Review IRB” and
earlier this summer. Quorum’s IRB registration number IRB00003226
Federal Regulation 45 CFR 46.103 requires those on the FWA. The written agreement can be an IRB
institutions that become engaged in research Authorization Agreement (either study-specific or an
conducted 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 an
provide written assurance. This is accomplished by IRB Authorization Agreement with Quorum, simply
submitting a Federalwide Assurance (FWA). For the complete the document located on Quorum’s
purposes of the FWA, federally-supported means the website and submit with your submission to
U.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 an
research study to an IRB, then likely the institution FWA, please see the Department of Health and
is “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 Federalwide
Recent revisions to the Terms of Federalwide Assurance.”3 Otherwise, Quorum is always available
Assurance for the Protection of Human Subjects to answer questions.
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
2
1
Federalwide Assurance for the Protection of Human Subjects, Federalwide Assurance Instructions, Step-by-Step Instructions
Terms of the Federalwide Assurance (FWA) for Institutions, for Filing a Federalwide Assurance, Item #6
3
Section 2 - Applicability http://www.hhs.gov/ohrp/assurances/forms/fwainstructions.html

3. August 1, 2011 | Volume 1, Issue 2
Regulatory Recap: bioequivalence and bioavailability studies conducted
to support the approval of generic drugs found at 21
FDA Issues Final Rule Regarding CFR part 320.5 Additional detail regarding the final
Safety Reporting Requirements rule is outlined in the FDA’s concurrent draft
guidance entitled “Safety Reporting Requirements
for IND and Bioavailability / for INDs and BA/BE Studies,”6 a FDA News
Bioequivalence Studies Release,7 and a FDA Q&A document.8
Safety reporting is critical to protecting the safety and The intent of the changes to the safety reporting
welfare of research subjects in clinical trials and is requirements is to “improve the overall quality of
important in developing accurate data on safety reporting, strengthen FDA’s ability to review
investigational drugs. Due to the undoubted critical safety information, improve safety
importance 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.”9
safety reporting requirements that is intended to Under the current regulations, sponsors are required
clarify such requirements. While the rule is for to notify the FDA and investigators, in an IND
sponsors and investigators, the rule also directly Safety Report, of any adverse experience “associated
pertains to Institutional Review Boards (IRB) that with the use of the drug that are both serious and
review clinical trials involving investigational drugs.
Below is a summary of the rule providing
5
information 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 new
requirements. regulations as soon as possible, and [] expect[s] all sponsors to be in
On 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/InvestigationalNew
Requirements 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/GuidanceComplianceRegulat
Bioavailability 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 a
March 28, 2011, amends the FDA’s regulations clinical trial. Available at
regarding 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 for
application (IND) found at 21 CFR part 312 and Investigational New Drug Applications (INDs). Available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugs
4
75 Fed. Reg. 59935 (Sept. 29, 2010). Available at areDevelopedandApproved/ApprovalApplications/InvestigationalNew
http://frwebgate.access.gpo.gov/cgi- DrugINDApplication/ucm226365.htm.
9
bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf. Id. at 1.

4. August 1, 2011 | Volume 1, Issue 2
unexpected and any finding from tests in laboratory context.13 The new regulations are therefore
animals that suggest a risk to human subjects.”10 The intended to address these concerns by clarifying the
language “associated with the use of the drug” is safety reporting requirements and articulating when
defined to mean that ‘there is a reasonable possibility it is sufficient to submit an IND Safety Report for a
that the experience may have been caused by the single event and when events should be submitted in
drug.11 Sponsors often interpret this to mean that the aggregate.14
they are required to report serious adverse
experiences as individual events even though it is Summary of the Final Rule
unlikely 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 the
events 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 adverse
According to the FDA, these types of events do not reaction.”16 A summary of the key definitions is
meet the definition of “associated with the use of the below. Additional information is contained in the
drug” and should not be reported in an IND Safety FDA’s draft guidance.17
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 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.

5. August 1, 2011 | Volume 1, Issue 2
Term/Phrase Definition Under the New Rule The FDA emphasizes, that before submitting an IND
Safety Report, the sponsor must ensure that the
Adverse
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) Suspected
Event 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 it
Adverse
Reaction
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 for
Suspected
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 definition
Adverse adverse event. For purposes of IND safety
Reaction 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, in
Unexpected 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 condition
18
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).

6. August 1, 2011 | Volume 1, Issue 2
under investigation or other events that commonly changes to the protocol, informed consent
occur in the study population independent of drug document, investigator brochure, “or other aspects
therapy) that indicates those events occur more of the overall conduct of the clinical investigation.”30
frequently in the drug treatment group than in a
3. New Requirement to Report Increased
concurrent or historical control group.”). These
Rate of Occurrence of Serious Expected
examples are discussed in detail in the FDA draft
Adverse Reactions
guidance.25
The rule includes a new requirement that the
2. New and Modified Requirement Regarding “sponsor must report any clinically important
Findings from Other Sources increase in the rate of the serious suspected adverse
The revised regulations include a new requirement reaction over that listed in the protocol or
to report findings from “other studies” that “suggest investigator brochure.”31 In determining whether or
a significant risk in humans exposed to the drug.”26 not to report, the sponsor may consider a number of
The phrase “other studies” includes “ongoing or factors “including the study population, the nature
completed clinical studies, polled data from multiple and seriousness of the reaction, and the magnitude
studies, epidemiological studies, and published and of the observed increase in the rate.”32
unpublished scientific papers.”27 The revised
4. Submission of IND Safety Reports /
regulations also include a modified requirement for
Reporting Format or Frequency
sponsors to submit IND Safety Reports for in vitro The submission timelines for submitting an IND
testing and clarification regarding the types of Safety Report remain unchanged, but do include a
findings from animal testing that must be reported.28 requirement that the sponsor submit to the FDA
Under the current regulations, an IND Safety Report “any additional data or information that the agency
is only required for any findings from animal testing deems necessary, as soon as possible, but in no case
which suggest a significant risk in humans. The final later than 15 calendar days after receiving the
rule therefore expands the reporting requirements. request.”33
The new and modified requirements require the
sponsor to promptly report findings for studies from 5. Investigations of Marketed Drugs
any 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 approved
noted by the FDA, such findings typically require in the United States under an IND for “suspected
adverse reactions observed in a clinical study” but
25
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).

7. August 1, 2011 | Volume 1, Issue 2
that they must also adhere to applicable Implications of the Revised
postmarketing safety reporting requirements.34 Safety Reporting Requirements
6. Reporting Study End Points With the emphasis being placed on whether or not
A requirement has been added to the final rule there is evidence to suggest a causal relationship
which states that “if a serious and unexpected between the adverse event and the drug and the fact
adverse event occurs for which there is evidence that the new requirements make clear the
suggesting a causal relationship between the drug circumstances for when it is appropriate to submit
and 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 the
unexpected suspected adverse reaction even if it is a final rule will reduce the number of uninformative
component of the study endpoint.”35 IND Safety Reports that are being submitted. As
noted in the draft guidance, “[t]hese clarifications
7. Investigator Reports
should increase the likelihood that submitted
According to the new reporting requirements, all
information will be interpretable and will
serious adverse events must be reported to the
meaningfully contribute to the developing safety
sponsor even if they are not related to the drug or
profile of the investigational drug and improve the
expected. 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 and
reasonable possibility that the drug caused the
reduce the number of redundant reports submitted
events.”36
to the IRB.38
8. Bioavailability and
This is not to say however, that challenges will not
Bioequivalence Requirements
exist. Sponsors and investigators will likely have to
The final rule includes a new requirement that
make changes to their policies and procedures in
requires a person conducting a Bioavailability or
order to comply with the new requirements. In
Bioequivalence study to notify all investigators and
addition, IRB’s will have to evaluate their own
the FDA about “any serious adverse event, whether
requirements and expectations regarding the safety
or not the event is considered drug related” as soon
reports received from investigators (and sponsors
as possible, “but in no case later than 15 days after
who submit on an investigator’s behalf). The FDA
becoming aware of its occurrence.”37
acknowledges that revisions to the current
investigator reporting requirements to IRBs may be
34
Revised 21 CFR 312.32(c)(4); necessary in order to address any issues that arise.39
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 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).

8. 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