Download - Understanding Reporting Obligatins to the IRB

fully accredited since 2006May 13 & 15, 2014

Understanding Reporting Obligationsto the IRB

Mitchell E. Parrish, JD, RAC, CIPRegulatory Attorney

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WEBINAR HOUSEKEEPING

• ABOUT QUORUM REVIEW IRB

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ABOUT QUORUM REVIEW IRB

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THE QUORUM ADVANTAGE

Quorum Review Regulatory AttorneyMitchell E. Parrish, JD, RAC,CIP

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ABOUT THE PRESENTER

IRB Experience Joined Quorum Review, Inc. in January 2010 CIP certification Regulatory Affairs Certification Member of Public Responsibility in

Medicine & Research (PRIM&R)

Legal Background Juris Doctor from University of Oregon Member of the Washington State Bar

Association (WSBA) Member of the Association of Corporate

Counsel (ACC) and Regulatory Affairs Professionals Society (RAPS)

Understanding Reporting Obligations To the IRB

Today’s Webinar:

Role of the IRB 11

Problems with Reporting 15

Regulatory Landscape 18

Obligations for Reporting Safety Information 26

Unanticipated problems that are Adverse EventsSUSARUADERecommended practices for reporting Safety Information

Obligations for Reporting Non-Safety Information 48Unanticipated Problems that are not Adverse EventsRecommended practices for reporting Non-Safety Information

Key Take Aways 62

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Topic Page

Webinar Overview

RoleIRB

of

The

the

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Role of the IRB

The primary purpose of both initial and continuing review of [a] study is ‘to assure the protection of the rights and welfare of the human subjects’ (§ 56.109(f). To fulfill its obligations… an IRB must have, among other things, information concerning unanticipated problems involving risk to human subjects in the study, including adverse events that are considered unanticipated problems.”

FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—Improving Human Subject Protection

(January 2009)

“

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Problemswith

Reporting

Problems with Reporting – Unnecessary Reporting

Much of the information that is being reported does not meet reporting requirements and therefore results in the unnecessary expenditure of resources by all stakeholders.

Specifically, “the way that ‘unanticipated problem’ is interpreted does not yield information about adverse events that is useful to IRBs and thus hinders their ability to ensure protection of human subjects.”

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“FDA Guidance for Clinical Investigators, Sponsors, and IRBs,

Adverse Event Reporting to IRBs—Improving Human Subject Protection(January 2009)

Problems with Reporting – No Explanation Provided

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Not only is unnecessary information reported, but also reported information is not explained:

FDA Guidance for Clinical Investigators, Sponsors, and IRBs,Adverse Event Reporting to IRBs—Improving Human Subject Protection

(January 2009)

“In the years since the IRB and IND regulations issued, changes in the conduct of clinical trials (e.g., increased use of multi-center studies, international trials) have complicated the reporting pathways for adverse event information described in the regulations. IN particular the practice of local investigators reporting individual, unanalyzed events to IRBs, including reports of events from other study sites that the investigator receives from the sponsor of a multi-center study—often with limited information no explanation of how the event represents an unanticipated problem—has led to the submission of large numbers of reports to IRBs that are uninformative.”

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RegulatoryThe

Landscape

Regulations (HHS/FDA)

• 45 CFR 46 (Protection of Human Subjects)

• 21 CFR 56 (Institutional Review Boards)

• 21 CFR 312 (Investigational New Drug Application)

• 21 CFR 320 (Bioavailability and Bioequivalence Requirements)

• 21 CFR 812 (Investigational Device Exemptions)

Guidance (HHS/FDA)

• HHS, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 15, 2007

• FDA, Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—Improving Human Subject Protection, January, 2009

• FDA, Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies, December, 2012

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Regulatory Landscape


FDA and HHS regulations require the IRB to receive safety and other information throughout study and during continuing review to ensure the criteria for approval is still met and to ensure the safety, rights, and welfare of subjects are protected

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45 CFR 46.109 and 46.111; 21 CFR 56.109 and 56.111

From Where is the Obligation to Report Safety Information to the IRB derived?


There is a lot of safety data and other information in clinical trials, so where in the regulations does it say exactly what to report to the IRB?

While the regulations do not contain specifics, they do provide the term “Unanticipated Problem” (UP)

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From Where is the Obligation to Report Safety Information to the IRB derived? (continued)

Regulatory LandscapeUnanticipated Problem

21 CFR 312.66 – “The investigator shall . . . Promptly report to the IRB . . . All unanticipated problems involving risk to human subjects or others.”

21 CFR 56.108(b)(1) – “[E]ach IRB shall: …Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problem . . . .”

45 CFR 46.103(b) (4) – An IRB must have “[W]ritten procedures for ensuring prompt reporting to the IRB , appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others. . . .

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Regulatory LandscapeUnanticipated Problem

Unanticipated Problem = Any incident, experience, or outcome that meets all of the following criteria:

Unexpected (in terms of nature severity or frequency) given(a) the research procedures that are described in the protocol-related documents, and (b) the characteristics of the subject population being studied

Related or possibly related to participation in the research

Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized

HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events

(January 15, 2007)

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*Note: This general criteria is essentially the same for unanticipated problems under FDA regulations as well.

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2

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Regulatory LandscapeUnanticipated Problems & Adverse Events

In addition to defining “Unanticipated Problem,” the HHS Guidance also explains that there are UPs that stem from adverse events, essentially safety related UPs, and those that do not stem from adverse events, essentially non-safety related UPs.

Adverse Event: Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in the research, whether or not considered related to the subject’s participation in the research. This encompasses both physical and psychological harms and can be categorized as “internal” (happening at the site) or “external” (happening at other locations).

FDA Guidance, Adverse Event Reporting to IRBs –Improving Human Subject Protection

(January 2009)

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Note: The terms “adverse effect” and “adverse experience” are interchangeable with “adverse event.”

Regulatory LandscapeUnanticipated Problems and Adverse Events

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Adapted from HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 15, 2007); See also FDA Guidance, Adverse Event Reporting to IRBs – Improving Human Subject Protection (January 2009)

• Safety Related:Do not report adverse events that are not UPs

• Non-Safety Related: Must report UPs that are not adverse events

• Safety Related:Must report adverse events that are UPs

Under 45 CFR 46 do not report A, do report B + C.

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Obligations for Reporting Safety Informationto the IRB

Regulatory LandscapeUnanticipated Problems and Adverse Events

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Under 45 CFR 46 do not report A, do report B + C.

Reporting Safety Information to the IRB

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SUSAR:SERIOUS & UNEXPECTED SUSPECTED

ADVERSE REACTIONS

UP:UNANTICIPATED PROBLEM

UADE:UNANTICIPATED ADVERSE

DEVICE EFFECT By its very nature, if an event is an SUSAR or a UADE then it is a UPand must be reported to the IRB

Reporting Safety Information - SUSARSerious and unexpected suspected adverse reaction (SUSAR) originates from 21 CFR 312and is designed to guide sponsors on when to submit IND safety reports to the FDA andinvestigators

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1. Serious (Death, life-threatening, inpatienthospitalization or prolongation of existing hospitalization,persistent or significant incapacity, substantial disruptionof the ability to conduct normal life functions, andcongenital anomaly/birth defect)

2. Unexpected (an event not listed in the investigatorbrochure or not listed at the specificity or severityobserved; or an event not consistent with the riskinformation described in the investigational plan)

3. Suspected Adverse Reaction (“a reasonablepossibility that the drug caused the adverse event”)Evidence to suggest a causal relationship between thedrug and event

Must report to the IRB all SUSARs that satisfy these three criteria:

Reporting Safety Information - SUSAR

Individual Occurrences

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)

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In a phase II study testing an investigational drug for Hepatitis C, a subject experiences hepatic injury. In addition to the investigational drug, the subject was continuing her standard Hepatitis C therapy at the time of hepatic injury.

Is this individual occurrence a suspected adverse reaction?

Example:


In a phase II study testing an investigational drug for Hepatitis C, a subject experiences hepatic injury. In addition to the investigational drug, the subject was continuing her standard Hepatitis C therapy at the time of hepatic injury.

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Is this individual occurrence a suspected adverse reaction?

Example:

YES


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One or more Occurrences

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,

progressive multifocal leukoencephalopathy)


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Is this one occurrence a suspected adverse reaction?

Example:

A subject with extrapulmonary small-cell carcinoma receiving an investigational chemotherapy agent experiences a bowel perforation during his second cycle of chemotherapy.


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Is this one occurrence a suspected adverse reaction?

Example:

A subject with extrapulmonary small-cell carcinoma receiving an investigational chemotherapy agent experiences a bowel perforation during his second cycle of chemotherapy.

NO


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Aggregate Analysis of Specific Events

An aggregate analysis of specific events observed

in a clinical trial (such as known consequences of

the underlying disease or condition 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.


17 oncology sites are participating in a research study comparing an investigational chemotherapy agent to standard therapy in subjects ages 60-85. Of those subjects receiving the investigational drug, an average of 35% of subjects across the 17 sites experience deep vein thrombosis.

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Example:

Does this aggregate analysis indicate a suspected adverse reaction?


17 oncology sites are participating in a research study comparing an investigational chemotherapy agent to standard therapy in subjects ages 60-85. Of those subjects receiving the investigational drug, an average of 35% of subjects across the 17 sites experience deep vein thrombosis.

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Example:

Does this aggregate analysis indicate a suspected adverse reaction?

YES


Critical to understand the definition of “Suspected Adverse Reaction” coupled with the examples the FDA provides:

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Individual occurrence

One or more occurrences

Aggregate analysis


Without this understanding, the FDAexplains that the following problem occurs:Reporting of individual events even though unlikely that the event was caused by the drug. Examples:

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Serious adverse experiences (e.g. mortality or major morbidity) that are unlikely 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 infarction 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)

Such reporting causes a “drain on resources” when the FDA, and IRBs are inundated with “generally uninformative” Safety Information especially when reported as single events without any context

Reporting Safety Information - UADE

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Unanticipated Adverse Device Effect (UADE) originates from 21 CFR 812 and is designed to guide sponsors on when to submit reports to the FDA and investigators

Must report to the IRB all UADEs that satisfy the following criteria:

Serious (death, life-threatening, serious problem)

Not previously identified (an effect not previously identified in nature, severity, or degree of incidence in the investigational plan or application)

Caused by, or associated with, a device

Reporting Safety Information - UADE

FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009)

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Individual occurrence One or more occurrences Multiple occurrences determined

through an aggregate analysis

Essentially states that reporting UADEs to the IRB should be treated the same as reporting SUSARs to the IRB

While not in the device regulations and while there are different considerations between safety information for drugs and devices, take into account whether the effect is a:

Recommended Practices for Reporting Safety Information

For Multi-center studies:

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FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009); FDA Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies (December 2012)

Even though the FDA regulations indicate it is the investigator’s responsibility to notify the IRB of unanticipated problems (21 CFR 312.66)—FDA guidance states: “Investigators must rely on the sponsor to provide them information about AEs occurring at other study sites”

“Although the investigator’s view of the causal relationship between an adverse event and the investigational drug is important, FDA believes that the sponsor is better positioned than the individual investigator to assess the overall safety of the investigational drug because the sponsor has access to serious adverse event reports from multiple study sites and is able to aggregate and analyze these reports.”

“The sponsor is in a better position to process and analyze the significance of AE information from multiple sites…and to make a determination about whether an AE is an unanticipated problem”

FDA supports an arrangement in which the sponsor prepares UP reports and submits to the IRB “when the sponsor, investigator, and IRB have made an explicit agreement for the sponsor to report directly to the IRB”


While Investigators may report SUSARs and UADEs to the IRB, Quorum recommends that Sponsors/CROs submit SUSAR and UADE information to the IRB on behalf of investigators. This means . . .

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(continued)

• The Sponsor/CRO should inform investigators and arrange with the IRB that it will report on behalf of investigators (arrangement with IRB should include in what format to report)

• The protocol should not state generally that “all adverse events require reporting the IRB” or include similar language because then if “all adverse events” are subsequently not reported, investigators run the risk of being out of compliance with the protocol

Also it is not appropriate to submit all AEs to the IRB, just AEs that are SUSARs or UADEs!


For single-center or investigator initiated studies:

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The investigator is likely the one reporting to the IRB

Also it is not appropriate to submit all AEs to the IRB, just AEs that are SUSARs or UADEs!

This still means: The investigator can arrange with

IRB in what format to report

The protocol should still not state generally that “all adverse events require reporting the IRB” or include similar language because then if “all adverse events” are subsequently not reported, investigators run the risk of being out of compliance with the protocol


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(continued)

Report SUSARs and UADEs “promptly” to

the IRB “Promptly” is generally considered 10 business days, which is supported in the FDA’s

guidance on reporting AEs to the IRB

This 10-day timeframe exists whether there is an arrangement for the sponsor to submit on behalf of the

IRB or whether the investigator is responsible for submitting to the IRB

TIMING of Reporting to the IRB


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(continued)

• What to report

• Whether to report

• How to report

• When to report

QUESTIONS ABOUT:

CONTACT the

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Obligations for Reporting Non-Safety

Informationto the IRB

Unanticipated Problems and Adverse Events

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Reporting Non-Safety Information to the IRB

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UNEXPECTED

UP:UNANTICIPATED

PROBLEM

You MUST report ALL UP’s to the IRB

GREATER RISK OF HARM

RELATED OR POSSIBLY RELATED

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• Failure to obtain informed consent• Major protocol deviations (e.g.

inclusion/exclusion violation; omitting a study procedure)

• Study personnel misconduct that adversely impacts the study

• Adverse findings by a regulatory agency, medical board, or other relevant body

Unanticipated Problems - Examples:

Are these UPs?

* Whether these are UPs depends on the type of study and the specific factors surrounding each event or incident

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An investigator is conducting behavioral research and collects individually identifiable sensitive information about illicit drug use by surveying college students. The data is stored on a laptop computer that is password protected. The laptop is stolen from the investigator’s car.

Is this reportable to the IRB as a UP?


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YES

An investigator is conducting behavioral research and collects individually identifiable sensitive information about illicit drug use by surveying college students. The data is stored on a laptop computer that is password protected. The laptop is stolen from the investigator’s car.



An Investigator is conducting a psychology study evaluating decision making and response times when persons are listening to music at various decibel levels. In order to perform the study, participants are placed in a small, windowless, soundproof booth. The IRB-approved protocol and consent form describe claustrophobic reactions as one of the research risks. The 12th subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the study.

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56


NO

An Investigator is conducting a psychology study evaluating decision making and response times when persons are listening to music at various decibel levels. In order to perform the study, participants are placed in a small, windowless, soundproof booth. The IRB-approved protocol and consent form describe claustrophobic reactions as one of the research risks. The 12th subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the study.



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As a result of a processing error by a pharmacy technician, a subject enrolled in a multi-center clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation.


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YES


As a result of a processing error by a pharmacy technician, a subject enrolled in a multi-center clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation.


Recommended Practices for Reporting Non-Safety Information

For multi-center or single-center:

Generally, UPs that are not an adverse event (i.e. non-safety related) are typically site or investigator specific

Therefore, it makes more sense for the investigator, not the sponsor, to report the UP to the IRB

The investigator can arrange with IRB in what format to report

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Recommended Practices for Reporting Non-Safety Information

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(continued)

Report UPs “promptly” to the IRB “Promptly” is generally

considered 10 business days, which is supported in the FDA’s guidance on reporting to the IRB

This 10-day timeframe exists whether there is an arrangement for the sponsor to submit on behalf of the

IRB or whether the investigator is responsible for submitting to the IRB

TIMING of Reporting to the IRB


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(continued)

• What to report

• Whether to report

• How to report

• When to report

QUESTIONS ABOUT:

CONTACT the

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KEYTAKE AWAYS

Key Take Aways

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• Know where the obligations to report to the IRB originate• Understand the term “Unanticipated Problem” (UP) and its three

criteria: Unexpected, Related, Greater Risk of Harm• Understand the terms SUSAR and UADE, know their criteria, and

know that these are UPs that require reporting to the IRB• Understand that there are UPs that are not safety‐related that must

be reported to the IRB• Know how and in what timeframe to report to the IRB• If there are ever any questions relating to reporting to the IRB, talk to

your IRB. The IRB is a resource!

• You may submit questions through our webinar survey

• Mitchell E. Parrish, JD, RAC,CIP– [email protected]– www.linkedin.com/in/mitchellparrish/

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fully accredited since 2006

Understanding Reporting Obligationsto the IRB

Download - Understanding Reporting Obligatins to the IRB

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