Protocol writing - for HANDOUTS (krisitn) Sept 07 · 7/30/2009 4 Key personnel to review the protocol Abstract, Protocol Body, Informed Consent, and Appendices Think about what you

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Anthea Atwell, RN, BSNAnthea Atwell, RN, BSNProject Manager, Research Education & Regulatory ManagementProject Manager, Research Education & Regulatory Management

What just happened???

Understand how the wording of protocol specific criteria impacts the ability to maintain compliance with the protocol.

Identify how to avoid protocol problem areas by incorporating lessons learned from previous audits.

Recognize how detailed source documentation can prevent unnecessary queries.

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FDA ‐Documents where information regarding the subject is first recordedthe subject is first recorded.

ICH ‐Original documents, data and records.

Hospital recordsClinical and office chartsLaboratory notesSubject’s diariesPharmacy dispensing recordsPharmacy dispensing recordsTranscriptionsMicrofilmRecords kept in other departments involved in the trialsPhotographic negativesX‐raysSubject files

Documents must be signed and dated in order to be considered a source

document!

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Allow verification of the existence of the subject.

Confirm that the data was accurately reported.y p

Confirm that the study was carried out according to protocol.

Important items to consider when reviewing a protocol that is already written

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Key personnel to review the protocolAbstract, Protocol Body, Informed Consent, and AppendicesThink about what you do in routine practice Think about what you do in routine practice compared to what is written in the protocolMake it as simple as possibleThink about how the item will be documentedMake sure that your protocol design will allow you to meet your protocol objectives

Protocol Deviations / Protocol Violations

Deviations Violations

Definition Not have a significant effect on the subject’s rights, safety, welfare,and or the integrity of the

May have a significant effect on the subject’s rights, safety, welfare, and or the integrity of the data and may cause an and or the integrity of the

datathe data and may cause an unanticipated problem to the subject or others.

Example Blood drawn on Day 4 rather than Day 3

Ineligible subject enrolled

Reporting Deviation logs reported to IRB annually at time of continuing review

Reported as soon as team is aware of the event

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Something every protocol is going to occasionally experienceKeep to a minimalKeep to a minimalWatch for repetitive deviations/ violationsDevelop corrective action plans when appropriate

When less can be moreWhen less can be more

versusversus

When more can be betterWhen more can be better

Eligibility CriteriaEligibility CriteriaBaseline / ScreeningEvaluation During StudyTreatment Plan

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The Gold Standard

If the investigator feels that it is important If the investigator feels that it is important enough to make it a

stand‐alone eligibility criteria an auditor will feel it is important enough

to source verify

Histologically or cytologically documented XXXX not amenable to surgical resection

At least 30 days since last dose of chemotherapy

Patients must have a life expectancy of at least 12 weeks

Negative pregnancy test (serum HCG) if female and of childbearing potential. Subjects must agree to practice effective birth control during the study period.

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Adequate renal function documented by serum creatinine of < 1.5 mg/dl

“Adequate renal function documented by serum creatinine ≤ upper limits of normal.”

Informed consent process

I l i it iInclusion criteria(lab values)

MDACC process for obtaining eligibility waiver

Only to be used when there is a minor deviation to eligibility criteria

▪ Required Hgb 10 – Pt Hgb 9.9▪ >/=30 days from last dose chemo – Pt at day 28

Requires approval from sponsor and IRB

Detailed instruction and required form located ▪ Clinical Research Homepage

Clinical Research Forms Section 1.101

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1. Be cognizant of the way you word your inclusion / exclusion criteria.

2. Know your criteria.

3. Know what you need to do in order to be sure that all criteria is source verifiable.


Procedure Timing

Informed Consent Obtain pt informed consent before any study specificprocedures are performed

Prior to any study procedures

Physical Exam Including Ht, Wt, Zubrod , VS Within 14 days of y g ystudy treatment

Hematology CBC with differential and platelets, PT/PTT

Within 14 days of study treatment

Biochemistry Ca, Na, K, CL, Phos, TP, Alb, creat, SAP, ALT, AST, LDH, BUN, t. bili

Within 14 days of study treatment

Cardiac Assessment EKG and MUGA scan Within 21 days of study treatment

HIV ELISA for HIV 1 Neg test within last 6 months

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Procedure TimingPhysical Exam Including: Ht, Wt, Zubrod,

VSPrior to each treatment

Hematology CBC with differential and l t l t PT/PTT

Each cycle on d 8 15 21platelets, PT/PTT days 8, 15, 21

Cardiac Assessment EKG and MUGA scan After every 3rd

cycleTumor assessment CXR, Chest CT, MRI of

brain, Bone ScanAfter every 3rd

cycle

Hint- Don’t paint your team in a corner. Give yourself some flexibility. (Example: Each cycle on days 8, 15, 21 +/- 1 day.)


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DOSE LEVEL DRUG “A”(mg/m2) IV

DRUG “B”(mg) PO TID

DRUG “C”(mg) IV

-2 80 140 100

-1 90 140 200

0 100 140 200

+1 100 140 400

+2 100 140 600

If dosing based on weight or BSA –▪ Are you using actual or ideal?▪ How often will you recalculate?

Following drug hold, the drug can be introduced when the g g , gtoxicity has “resolved” = baseline vs normal vs grade 1?

Can dose be re‐escalated?

For lengthy drug hold, when must patient come off protocol?

When do you need to hold or dose reduce study drug?

How have you defined Dose Limiting Toxicity (DLT)?

How will you track drug compliance when…y g p▪Drug is given in house or in clinic?▪Drug is self administered?

What is the percentage compliance needed to stay on protocol?

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Write what you want…Write what you want…

Do what you writeDo what you write

Study accrual and treatment schedule are not consistent throughout documents

Drug names are not consistent throughout g gdocuments

All risks associated with an agent and/or treatment information not included in the ICD

Appropriate rationale for exclusion of certain populations not provided

Clarifications related to cost of study agent/procedures

Interim analysis/monitoring plan not provided

No plan for de‐identification of blood/tissue samples

Typos

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10. Research practice is not medical practice.

9. While writing the protocol, avoid the temptation to cut and paste.and paste.

8. Just because a concept was used in a previous protocol does NOT mean it was a great idea.

7. Have a colleague, senior research nurse and experienced data coordinator read your protocol prior to submission.

6. The faster the accrual, the larger the headache.

5. The speed of publication is inversely proportional to the complexity of the protocol.

4. Each day only has 24 hours no matter how superhuman the effort. It is better to manage a few protocols well than many protocols poorly.

3. Protocol violations/ PI overrides are not an “alternate method” for patient enrollment.

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2. Treat your patient with respect:

“Hell hath no fury like a patient complaint to the y p pFDA.”

And the #1 thing for a successful protocol……..

Always appreciate the ff t f h efforts of your research

team. They are the unsung heroes of a study that is well done.

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Additional Questions…

Phone: 3‐[email protected]

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Overview of Adverse Events

Gloria Morris, RN, CCRC, CCRASr. Project Manager-IND Safety

Office of Research Education and Regulatory Management July 2009

Objectives

Define: adverse events (AEs)serious adverse events (SAEs)expected / unexpected events

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expected / unexpected events

Determine: attribution of event

Understand: timelines for following and reporting SAEs

Adverse Event Definition

Any event that is unfavorable or unintended that occurs after the administration of a drug, biologic, or

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administration of a drug, biologic, or device regardless of whether it is considered related to the medical treatment or procedure.

• Worse than baseline• Importance of baseline assessment

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Terms used for “AE”Adverse Experience (AE)

Adverse Drug Reaction (ADR)

Adverse Drug Experience/Event (ADE)

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Adverse Reaction (AR)

Adverse Device Effect (ADE)

Side Effect (SE)

Safety Information

Toxicity

Why is all of this

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of this information important?

Consequences

• Protocol violations• Protocol closed by IRB

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• Protocol put on hold by FDA• Protocol closed by sponsor• Research priviledges revoked

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What does the _____ do with the AE information?

• Patient level of risk?

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• Significant protocol toxicity?• Study continuation?• Protocol review interval?


• Analyzes risks/benefits

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• Updates Investigator brochure• Informs federal regulatory agencies• Ammends package labeling

Key elements of AEs

1. Grade2. Attribution

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3. Expected/unexpected

• Serious?• Required type of reporting?

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1. Grade / Severity

• Numerical value between 1 and 5

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• Number assigned by referencing a grading criteria

• NCI CTCAE version 3.0

2. Attribution

• Aka “relationship” or “causality” or “drug related assessment”

• A determination made by a clinical

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A determination made by a clinical investigator that describes the relationship or association of the study product with an adverse experience

• Note: At MDACC, this responsibility cannot be delegated to research staff

MDACC/NCI categories of attributions

• Unrelated - is clearly not related to study agent

• Unlikely related is doubtfully related to study agent

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• Unlikely related - is doubtfully related to study agent

• Possibly related – may be related to study agent

• Probably related – is likely related to study agent

• Definitely related – is clearly related to study agent

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Questions to Help Determine the Relationship to Study Drug

• Is it a known side effect that can occur with the use of the drug?

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• Is there another explanation for the adverse experience?

• What is the timing of events or is timing appropriate for the event?


• What are the drug levels?

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• What happened to the adverse experience when the drug was decreased or stopped?

• What happened when you rechallenged the patient with the drug?

3. Types of Adverse Events• ________________ Events **“known” eventslisted in drug information

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• ________________ Events **“unknown” eventsnot listed in drug information

** not a patient assessment;only based on drug information

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Recording

• Review protocol for requirements• AE data may be received in numerous

ways from various sources

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y• AE data may be collected by many

different employees

• Organization, communication, and timing is key!

Recording tips• Always need start and stop date of AE

• Timing: last dose?

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last dose? when notified?

• Interventions: dose modified or stopped? patient withdrawn?medication / medical interventions needed?

Reporting Adverse Events

• ________________ reportingDescribe events in write up of protocol findings usually at study

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protocol findings-usually at study end or interim analysis.

• ________________ reportingImmediate reporting of events to specified individuals, committees or agencies.

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Clarificationof SAE

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of SAE Terms and Definitions

Terms used for “SAE”

• CFR - Serious Adverse Drug Experience (SAE)

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• CFR Proposed – Serious Suspected Adverse Drug Reaction (SADR)

• ICH – Serious Adverse Event (SAE) or SeriousAdverse Drug Reaction (Serious ADR)

• NCI – Adverse Event

SAE Definition(based on one of the outcomes listed below, not a certain grade

or attribution)

Any adverse drug experience occurring at any dose that results in any of the following outcomes:

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1. Death2. Is life threatening3. Requires inpatient hospitalization or

prolongation of existing hospitalization4. Persistent or significant disability or

incapacity5. Congenital anomaly / birth defect

• Other important medical event

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Terms as related to SAEs

• Expected versus unexpected• Life threatening

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• Expedited versus routine• Initial versus follow-up• “Other”

SAE Categories

“Expected versus “Unexpected”“Internal” versus “External”

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Internal versus External

• Affects type of reporting required• Affects type of form used• Affects who receives report

___________ SAE Events

• SAEs that occur at the MD Anderson (MDACC) site

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• Affects all patients enrolled on MDACC protocols

• Includes patients enrolled here, but receiving part of their care elsewhere

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_____________ SAE Events• SAEs that are reported to the PI through the

sponsor, because an unexpected SAE that has been determined to be related to the drug has occurred at another site with the

t d d

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same study drug

• May not be same protocol or use for drug, but only same agent being used

• “Other site” can also mean another MDACC investigator / department

Reporting by PI

For internal SAEs:Always:• By PI to IRB• By PI to Sponsor (if there is one)

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Sometimes:• By PI to MDACC (ORE&RM)• By PI to Manufacturer

For external SAEs:• Always by PI to IRB (from info received

from study sponsor)

Reporting by Sponsor

For internal SAEs:Always:• To FDA

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Sometimes:• To IBC (Institutional Biosafety Committee)• To RAC at NIH

(Recombinant DNA Advisory Committee at National Institutes of Health)

For external SAEs:• Always: To other sites

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Research demands involvement.It cannot be delegated very far

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It cannot be delegated very far.Anonymous

Minimum Reporting Timeframes at MDACC

• Usually 24 hours for reportable deaths **

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• 5 working days for all other reportable SAEs **

** Days are counted from date of knowledge of the event

Reporting SAEs

30 Day Rule

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All reportable events that occur within 30 days of receiving last dose of study drug must be reported according to guidelines

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Which guidelines to use?

Follow most stringent guidelines for your individual protocol

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1. Protocol and/or appendices2. Sponsor requirements3. MDACC / IRB Guidelines4. Code of Federal Regulations

Patient

Research Nurse, PI,Data Manager

Cycle of reporting of event

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Data Manager

IRB Sponsor

All sitesFDA

Forms for SAE Reporting

• Sponsor Forms• IRB Forms and logs (available on-line or from IRB)

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(available on line or from IRB)• On-line reporting

Watch for inaccuracies, missing key data, discrepancies, and incorrect information

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Key elements of AEs

1. ___________2. ___________

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3. ___________/____________


References

• On-line alphabetical index

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• Computerized “safety profiler”• On-line references• MDACC Phone contacts

Alphabetical Indexhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcae_index.pdf

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Computerized Programhttp://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx

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On-line References

• MDACC IRB (Human Subjects Manual)• For MDACC IND Studies-SOPs at Intranet site: Investigational New Drug (IND) Office

• Regsource.com-see “Code of Federal

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gRegulations” 21 CFR § 312.32 - INDsafety reports, definitions

• FDA-www.fda.gov• NCI- http://ctep.info.nih.gov• ICH-www.ich.org• Sponsor’s website

Institutional References• MDACC IRB Help line: 792-2933 or “IRB help” in Lotus Notes

Human Subjects Manual On-Line – forms, logs and guidelinesGeneral questions and questions re: log Mira Shah 563-5437

• Submit External SAEs to Mary Fields 563-5441• Submit Internal SAEs to Rosa Jaramillo 563-5443

• For studies with Pharmaceutical Sponsors:

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Study monitor, protocol contractSponsor’s written guidelines for CRFs, SAE reporting

• NCI Studieswww. cancer.gov-printable copy of CTC criteria and alphab. indexSylvie Marcy 563-5456

• For MDACC IND StudiesORERM SOPs for IND Studies – Intranet site under: “Investigational New Drug (IND) Office”Study monitor, or Gloria Morris 563-0379

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Thank you!


Office of Research Education and Regulatory Management [email protected]

713-563-0379

AE policy 1 Revised 3/25/09

University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious Adverse Events

PURPOSE It is the policy of The University of Texas M.D. Anderson Cancer Center

Institutional Review Board system (UTMDACC IRB) to comply with the regulations governing human subjects’ research.

POLICY STATEMENT

The purpose of this policy is to protect human subjects’ safety by mandating that investigators report adverse events, involving risks to subjects and others, to the UTMDACC IRB system. The UTMDACC IRBs review and act on reports of adverse events to determine:

• if the risk-benefit ratio continues to be acceptable; • if the research protocol and informed consent document accurately

and completely presents the risk information to research subjects; • if subjects already enrolled should be advised of newly identified

risks and/or be re-consented. SCOPE This policy applies to all clinical trials conducted at UTMDACC involving

investigational new drugs, commercially available drugs, biologic products, devices, behavioral science, laboratory and chart reviews.

DEFINITIONS Adverse Event (AE) – 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. For minimal risk studies such as behavioral science, laboratory, and epidemiologic protocols, as well as chart reviews, reasonable judgment must be used to determine what constitutes an AE. Expected AE - Any AE with specificity or severity that is consistent with the current Investigator Brochure (IB) or consistent with the risk information described in the Informed Consent Document (ICD) or general investigational plan. All clinical protocols should include a list of the expected and anticipated events or hospitalizations relating to the study treatment. Unexpected (Unanticipated) AE - Any AE, with specificity or severity that is not consistent with the current IB or not consistent with the risk information described in the ICD or general investigational plan.


Serious Adverse Event (SAE) – Any AE associated with the subject’s participation in research that:

• results in death; • is life-threatening, (places the subject at immediate risk of death

from the event as it occurred); • results in inpatient hospitalization or prolongation of existing

hospitalization; • results in persistent or significant disability/incapacity; • results in a congenital anomaly/birth defect; or • based upon appropriate medical judgment, may jeopardize the

subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Internal AE - An AE occurring in a subject who is enrolled in a protocol or study that is under the oversight of a UTMDACC IRB. External AE – An AE occurring in a subject who is not enrolled in a UTMDACC protocol or is on a protocol at a site that is under the oversight of another IRB. Generally, the PI has received notification of this AE from the protocol sponsor. Example: Medwatch report, CIOMS report, Safety reports. Related: Events directly or indirectly attributed to study drug, device or procedures and/or study participation. Events occurring with sufficient frequency to suggest that they are not random. Unrelated: Events that would occur regardless of study participation, including events that are clearly random occurrences. If the frequency of the event suggests a possible connection to the study intervention, then it should be considered related. AE Attribution - The determination of whether an AE is related to the research (medical treatment or intervention): Definite – It is clearly related Probable - It is likely related Possible - It may be related Unlikely - It is doubtfully related Unrelated - It is clearly NOT related AE Severity - Refers to the intensity (grading) of a specific AE. All clinical trials conducted at UTMDACC must use the “CTCAE v3.0 grading scale” for AE documentation and reporting (Publish date June 10, 2003). For the purpose of this policy, toxicity is synonymous with AE.


Minimal Risk - Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of a routine physical examination, physiological examination or laboratory testing. Designation of minimal risk will be determined by the IRB at the time of initial approval and reviewed at least annually during continuing review.

Multicenter Studies Since UTMDACC PIs participating in multicenter trials are unable to prepare a meaningful summary of SAEs, at the time of continuing review they should submit the current report from the monitoring entity (e.g. research sponsor, coordinating statistical centre, or DSMB/DMC). The report should include the following:

• a statement as to what information was reviewed by the monitoring entity (e.g. study-wide AEs, interim findings, recent literature relevant to the research);

• date of the review; • monitoring entity’s assessment of the information. Information that

is considered inadequate by the PI should be returned to the monitoring agency/sponsor for completion.

Institutional Procedures

Reporting Requirements for Internal AEs

Serious Internal AEs (SIAEs) requiring prompt reporting to the IRB All internal AEs that include all of the following will require prompt reporting to IRB via the Office of Protocol Research (OPR):

• Serious • Unexpected • Related (definitely, probably, or possibly related) to participation in

the research. Timeline for prompt reporting: 1. Within 1 working day (24 hours) from the time the research team

becomes aware of the event = Deaths that are unexpected and definitely, probably or possibly related to study intervention that occur during and within 30 days after the last day of active study intervention.

2. Within 5 working days from the time the research team becomes

aware of the event = All other serious, unexpected and definitely, probably or possibly related AEs.

SAEs will require prompt reporting from the time protocol specific consent is signed, and screening has begun, during the course of study intervention and within 30 days after the last day of active study intervention. Beyond 30 days of study intervention, completion of only those SAEs that, in the judgment of the investigator, are related to research will require prompt reporting.


SIAEs Requiring Documentation on AE Log: All SIAEs that do not fall under the prompt reporting requirements should be reported during continuing review using the Internal SAE Log or database printout. Note: If a trend or recurring adverse events are seen, the PI should report these events using the Internal SAE report Form for prompt reporting. Individual reports submitted to IRB that do not meet the requirements for prompt reporting will be returned to PI.

NOTE: Certain types of incidents, experiences, and outcomes that occur during the conduct of research are unexpected, related or possibly related to the research, and place the research subject at a greater risk of harm but are not considered adverse events. These incidents are classified as unanticipated problems and will require reporting to the IRB. These have different reporting forms and are discussed under the "Policy on Reporting Protocol Deviations, Protocol Violations, and Unanticipated Problems."

Reporting Requirements for External AEs

Serious External AEs (SEAEs)Requiring prompt Reporting to IRB ONLY those external AEs that include all of the following will require prompt reporting to the IRB via OPR

• serious, • unexpected, • related (definitely, probably, or possibly related)

Reporting Timeline for prompt reporting: 1. Within 5 working days from the time the research team becomes

aware of the event = Unexpected deaths that are attributed by the Sponsor as definitely, probably or possibly related to study intervention that occur during and within 30 days after the last day of active study intervention.



SEAEs are required to be reported to the IRB beginning on the date of the UTMDACC IRB approval letter of the associated protocol. EAEs Requiring reporting to IRB using External AE Log: All SEAE that do not fall under the prompt reporting requirements should be reported using the External SAE Log or database printout or summarized and submitted during continuing review. Individual reports submitted to IRB that do not meet the requirements


for prompt reporting will be returned to PI.


This policy does not replace the reporting requirements to the FDA, the sponsor or monitoring agency.

Reporting Requirements for trials involving minimal risk

Reporting for trials involving minimal risk For protocols designated as minimal risk, AEs considered serious, unexpected and definitely, probably or possibly related to the study must be reported promptly as described above. [AEs considered to be unrelated to the study and non-serious AEs must be reported during continuing review (annual report)].

Reporting of SAEs for Terminated Protocols

Reporting of SAEs for Terminated Protocols Only those serious AEs that were unexpected and may impact the health, welfare or safety of subjects must be reported. For example, submit reports of secondary malignancies or problems with implanted devices.

Forms A written report will be submitted to the UTMDACC IRB using one of the

following forms: Internal SAE Report Form for Prompt Reporting: The Internal SAE Form should be utilized to report events that occur to subjects enrolled on a UTMDACC protocol/study. Internal SAE Addendum Form for Prompt Reporting: May be completed if the protocol sponsor requires a protocol specific form to be completed for subjects enrolled on a UTMDACC protocol/study, i.e., Medwatch report, CIOMS report. This addendum should be completed and attached to the sponsor form for submission. Departmental External SAE Report Form for Prompt Reporting: External SAEs of single or multiple protocols using the same drug, within a department can be submitted using the Departmental External AE Form for Prompt Reporting. Internal SAE Log All AEs not requiring prompt reporting to the IRB have to be listed on this log or a database print out with the same information can be submitted during continuing review. External SAE Log All AEs not requiring prompt reporting to the IRB have to be listed on this log or a database print out with the same information can be submitted during continuing review.


Safety Summary Report Submission Memo All external safety summary reports/alerts containing multiple AEs that briefly describe each event as updates received from the sponsors must be submitted using the safety report submission memo.

Form Completion

1. All the forms must be completed in full. 2. Protocol status must have only one choice. 3. If the SAE is noted as “ongoing” at the time of initial reporting, a follow-

up report will be required when the outcome of the SAE is known or when the event is considered to be permanent.

4. For follow-up reports, the date that the research team is notified should be the same as that of the initial report and the date submitted should be the actual date the follow-up report is submitted.

5. A concise synopsis describing the event must be provided. For follow-up reports, an updated synopsis must be provided.

6. If a report is being submitted outside of the stated time frames in this policy, a justification must be provided. (Note: failure to report an SAE in time may be considered a violation and repeated occurrences may constitute “continuing non-compliance”)

7. For reasons of confidentiality, subject names must NOT be included in any report or must be blacked out on patient reports. Subject identifiers such as patient ID or accession numbers should be used instead.

8. All report forms must include the attribution of the event. 9. The report form must be signed by the PI. The form can be signed by

the attending physician, but only when the PI is not available. All forms are located in the Human Subject Research Manual under Chapter 15.

REFERENCE: 21 CFR 56.108(b) 45 CFR 46.103 21 CFR 310.305 45 CFR 46.109 21 CFR 312.32 45 CFR 46.111 21 CFR 314.80 45 CFR 46.113 OHRP and HSS Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 25, 2007 Committee Review Committee: Names: Date: Institutional Review Board 3 Richard L. Theriault, D.O.

Ralph S. Freedman, M.D. Linda S. Elting, Dr. Ph.

November 1, 2006

Committee: Names: Date: Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. March 26, 2008 Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. April 23, 2008 Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. March 25, 2009

12/20/2007

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The University of Texas

M. D. AndersonCancer Center

Updated: December 2007

Scientific Review SpecialistOffice of Protocol Research

Scientific Review & Approval Process for

Protocols

Scientific Review Team

Mira Shah, CIM Manager x 3-5437

Jenny Gay, BS Supervisor – Scientific Review (CRC) x 3-5438

Angela Culler Project Leader – PRMSAAC / DMC x 3-5439

Carol Hemenas PBHSRC / PRMSAAC Specialist x 3-4709

Shapatra Parker, MS CRC 1 Specialist x 2-0320

Roxanna Zarate CRC 2 Specialist x 2-7881

Shakia D. Jones CRC 3 Specialist x 2-9959

Michelle Almarez, BBA CRC 4 Specialist x 2-6490

Michelle D. Linares, CPhT DMC Specialist x 2-1875

Email through Lotus Notes: CRC PBHSRC Help Desk

Abbreviations

OPR = Office of Protocol Research

CRC = Clinical Research Committee

PBHSRC = Psychosocial, Behavioral, Health Services Research Committee

IRB = Institutional Review Board

PDOL = Protocol Document On-line System

NCI = National Cancer Institute

PI = Principal Investigator

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Clinical Research Committee (CRC)Clinical Protocols, and High Risk Labs

Psychosocial, Behavioral, & Health Services Research Committee (PBHSRC)Behavioral Science Protocols, Questionnaires,

Surveys, etc.

Scientific Review Committees

What is a Protocol ?

A protocol is a document that describes the objective(s), design, methodology, statistical considerations, and organization of a

trial. A protocol is used for conducting and evaluating an investigation.

Any research performed at MDACC that pertains to human subjects or human specimens must be

approved by the Institutional Review Board.

Includes: Clinical Trials

Questionnaires or Survey

Lab Research

Data Reviews

Who can be listed as a Principal Investigator ?

PI for Clinical ResearchMDACC Faculty Member

Co-PI for Clinical / Behavioral ResearchMDACC Faculty Member

FellowsStudents

PI for Patient Care / Behavioral ResearchMDACC Faculty Member

Advanced Practice Nurse (APN)Nurse Managers

PharmacistsDieticians

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NOTE: The PI must have the Adequate Training & have MDACC as their Primary Appointment. All other collaborators also must have the appropriate

training.

See the Clinical Research Home Page, Human Subject Research Manual,

Chapter 4, Section 4.0 Training Requirements.

Training Requirements

Useful Tools

Have a question about the CRC/PBHSRC? • Deadlines

•Meeting Dates • Need a form

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The easiest way to producea new protocol.

• MDACC

• NCI

• Pharmaceutical Sponsored protocols

Please contact 5-PDOL (5-7365) for class information.

PDOL System

Required Items:

• Protocol number (obtained through PDOL)

• Department Head Approval Form

• Original signature pages (Electronic or Hard Copy)

• MDACC protocol abstract

• Protocol Body (PDF/Word attachment)

• Appendices

• Informed Consent/Authorization

Required MDACC Appendices

• Common Terminology Criteria for Adverse Events v3.0 CTCAE (not needed for PBHSRC protocols)

• Protocol Checklist (Dated: 11-2005)

• Prioritization List

• Investigator’s Brochure for Treatment Related Protocols only: (If an IND is involved with the study, then please attach the I.B. and have the PI sign electronically)

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•Two Medical Reviewers•Biostatistics (Not needed for COOP and NCI protocols)

•Pharmacy (Not needed for PBHSRC protocols)

•Radiology (Not needed for PBHSSRC, COOP and NCI protocols)

•Nursing (Not needed for PBHSRC and COOP protocols)

•IND Admin Review (Institutional IND Review Committee will determine if your protocol needs to have an IND or an exemption )

•OPR Admin Review• Informed Consent Review (All informed consents are reviewed and edited by the OPR Scientific Editors)

Peer Review System

Protocols are reviewed by:

Points to Consider On the MDACC ABSTRACTObjective Section:

•Please make the protocol and abstract match.

Inclusion / Exclusion Criteria :

• Please make sure that it matches the protocol.

•Do not copy and paste signs over into PDOL. (Ex: > or < instead type in >/= or </=)

•Superscripts just use ^ (Shift 6 key). (Ex: 10^6)

•Subscripts will need to be typed out.

•Please do not refer to the protocol & appendices. (Ex: see section 10.2 or see appendix a)

Points to Consider On the MDACC ABSTRACT:

•Is there an age limit? Yes/No

Why? Provide Scientific Justification

•Estimated Accrual:

Total Accrual at MDACC:

Estimated monthly accrual at MDACC:

Total accrual will be:

(Only applicable for Multi-center or Cooperative Group)

12/20/2007

6

• Any Principal Investigator who submits a new protocol will be required to review a protocol during the same submission period.

• In the event that a Principal Investigator is unable to provide a protocol review that s/he was assigned to, then their own protocol will not proceed until they have provided a protocol review for our office.

First Medical Reviewer

Submit One, Review One Policy

• As of Sept 2005, PI’s will need to supply 2 names of faculty members who have agreed to do a protocol review. (This can be found at the bottom of the Dept. Head Approval Form)

• Committee Members may also be selected for the review process.

Second Medical Reviewer

Chair assigns reviewers & the Protocol is then sent out to reviewers 2 - 3 days after submission deadline (Friday)

P.I. submits protocol by Noon on the day of Submission Deadline (Tuesday)

The PI has 2 days to respond & make all changes and protocol is resubmitted( Deadline 5 pm Tuesday)

If Approved or Approved w/ Minor Contingencies, the protocol proceeds to the IRB

Protocol maybe reviewed at the next CRC / PBHSRC meeting

Reviewers have 1 week to complete a protocol review (Friday to Friday – 5 pm deadline).

Changes made to protocol documents are then reviewed by OPR Specialist

Chair reviews protocol documents and sets the agenda

12/20/2007

7

• Copy of the most current Abstract

• All Reviews and PI’s Responses

• Resubmission Memo outlining the changes

At the Meeting, Committee

Members are given:

What happens at the meeting?PI, Co-PI, or Department Chairpresents protocol to Committee

Committee reviews reviewer’s concerns & PI’s responses & asks questions

Protocol is discussed

Presenter is asked to wait outside the room while the committee votes on the protocol

Presenter is notified of the outcome and an outcome memo is sent to PI

Protocol Disposition

The protocol can proceed to the IRB if:

• Approved As Is

• Approved w/ Suggestion or Recommendations

• Approved w/ Contingencies: Can Proceed to IRB Without Modification (Minor Contingencies - typographical errors)

12/20/2007

8


Requires Modification Before Proceeding to IRB (Major Contingencies)

Goes to IRB when:

• PI Submits the revised protocol to OPR with a detailed memo outlining changes. The changes should ONLY pertain to the meeting contingencies.

• Once contingencies have been met, the protocol is then approved by the CRC/PBHSRC Chair and then sent to the IRB.


Deferred

Rejected

• PI submits a revised protocol to OPR to address the contingencies.

• Chair reviews revised protocol.

• The PI is then notified that s/he will need to present their protocol back to the same committee. (Example: Presented at the CRC I and deferred, then the PI will need to go back to the next CRC I meeting)

• Study cannot be conducted at MDACC.

Training Course

The Scientific Review Team offers group / departmental training. If you would like for us to come and do an informative training session, please contact us by telephone or email at:

• 713-792-2933

•Lotus Notes: CRC PBHSRC Help Desk

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IRB Processes & Helpful Hints

2009

Rachel AvantsIRB Education Coordinator

Objectives

• Explain how the IRB functions at MD Anderson• Provide instruction on submitting revisions to

Protocols• Give an overview of the Continuing Review• Give an overview of the Continuing Review

process that Protocols undergo annually• Review requirements for the submission of

laboratory, data review and exempt research

What is the Institutional Review Board?

The IRB is a federally mandated committee that has the authority to approve, require

modification to, and disapprove all research activities that fall within its jurisdiction, as specified by both federal regulations andspecified by both federal regulations and

institutional policy.

Note: UTMDACC has approximately 4,200 protocols

that are subject to IRB review

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IRB Meeting Designations

IRB1, IRB2 and IRB5: Responsible for reviewing clinical research activities

IRB3 R ibl f i i d tti li

As of September 1st, 2007, there are five (5) IRB committees in operation at UTMDACC:

IRB3: Responsible for reviewing and setting policy, including safety information pertaining to human subjects research conducted at UTMDACC.

IRB4: Responsible for reviewing health services, behavioral science and psychosocial research activities

**Note: IRB Meetings are closed to non-committee members**

A study has been designated for IRB review.

What happens next?

Initial IRB Review

Following CRC/PBHSRC review, the protocol is assigned to the next IRB meeting

The study is assigned to an IRB committee member for presentation

OPR Scientific Editor finalizes the Informed ConsentOPR Scientific Editor finalizes the Informed Consent prior to the IRB meeting

The protocol is presented at an IRB meeting and discussed by the committee

After the committee’s discussion, a formal outcome is decided for each protocol

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IRB Initial Protocol Outcomes

Approved – Protocol can proceed and PI may request activation

Contingent – The study requires minor changes that must be addressed, prior to receiving outright IRB approval

Deferred – Substantial changes are required, prior to receiving outright IRB approval

Disapproved – The study in its current format cannot be conducted at UTMDACC

Following the IRB meeting, the PI will receive formal written notification of the study’s outcome,

as soon as it is available.

Disapproval Responses

A PI can submit a formal response to the IRB, in order to justify the social and

scientific value of the studyscientific value of the study. The IRB committee will review a

PI’s response on acase-by-case basis.

Initial IRB Review

IRB Approval

Flow of IRB Review

Revisions/Amendments Can Now Be Submitted

IRB Approval

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The study has received IRB approval and a revision needs to be submitted.

Revisions

The IRB must review and approve all revisions/amendments before changes

can be implemented.

What is a Revision/Amendment?

A revision is a change made to any IRB approved protocol

A revision can be initiated by:PI

Study Sponsor

Required by the IRB

A protocol does not require activation prior to a revision being submitted.

Required Format for IRB Revision Submissions

Each revision listed in the resubmission cover memo should contain the following information:

DocumentS ti ( b d f ti )Section (number and name of section)ParagraphPageOld TextNew TextScientific Rationale

5

Example – IRB Revision Entry

»»» Revised Text # 1

Document: Protocol Body

Section: 5.0 Treatment

Paragraph: 1

Page: 9

Old Text: Study participants will receive two to three treatments per week.

New Text: Study participants will receive two to five treatments per week.

Scientific Rationale: Adjustment of treatment regimen allows us to account for varying reactions to treatments.

IRB Revision Outcomes

Approved: Changes are acceptable as written and no further changes are requested.

Contingent: Requires minor changes that must be addressed, prior to receiving outright IRB approval.

Deferred: Requires substantial changes, prior to receiving outright IRB approval.

Disapproved: Revision in its current format cannot be implemented at UTMDACC.

Protocol ActivationProtocol Activation

Once a study has been approved, the PI must submit a request protocol activation

h h PDOL hthrough PDOL to the Office of Protocol Research.

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Additional Items That Require IRB Review

Advertisements

Protocol Brochures

Recruitment Materials

Deviations

Violations

Terminations

Withdrawals

Per Federal Mandate, all human subjects protocols must be reviewed at least once every 365 days,

from the last IRB approval date.

45CFR §46 109( ) “A IRB h ll d

Continuing Review of Protocols

45CFR §46.109(e) “An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research.”

Countdown begins the day the protocol is IRB approved.

For example:

A l 3 2006

Important to Remember . . .

IRB Approval Date: January 3, 2006

Activation Date: July 15, 2006

CR Must be Completed by: January 3, 2007

Protocols that are closed to new patient entry still go through the continuing review process.

7

CORewww.oncologyresearch.org

Username and Password

713-745-2673 (5-CORe)[email protected]

Termination (final report must be attached)

Withdrawal (the study was never activated)

Items that may be requested atContinuing Review

Close Study to New Patient Entry

PI may be changed (Revised title page, abstract and informed consent must be submitted with Continuing Review form.)

Final ReportIf termination is requested at Continuing Review, please include the following:

Hypothesis

Objectives of Study

Method

Statistical Considerations

Results

Conclusion/Outcome

Implications

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Helpful Hints for Completing Your Continuing Review

If the study does not have toxicity or a response to treatment, select “N/A”

Make sure the number of participants / d i d/ hseen/records reviewed/etc. are shown

somewhere on the review.

If number of records reviewed exceeds max accrual, please revise your protocol

What if I want to review human subject specimens and/or medical

records?

Laboratory Protocols

Lab protocols involve the analysis of human subject specimens for research purposes.

Lab protocols can be performed prospectively orLab protocols can be performed prospectively or retrospectively.

Lab protocols MUST be submitted to the IRB for approval and activation, prior to the intended research being performed.

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Prospective Lab Studies

Tissue and/or samples will be obtained from living individuals

a. Protocol-Defined Samples (collected solely for the purpose of the lab study)

b. Additional Material/Extra Sample (collected for research purposes during a normally scheduled clinical procedure or test)

Since the research plan is known prior to obtaining tissues/samples, this type of study typically requires a study- specific informed consent.

Retrospective Lab Studies

Existing tissues/samples obtained for purposes unrelated to the submitted protocol. Can either be --a. Archived samples from an MDACC Institutional Tissue Bankb. Residual samples (fresh material left over from a routine diagnostic test or procedure)

Utilize a Waiver of Informed Consent and Waiver of Authorization to Use and Disclose Protected Health Information

Waivers should document that study participants’ consented to the use of their tissue/specimen for future research. The Waivers should include the original Protocol Number or mechanism under which the samples were obtained.

Prospective Data Reviews

Data from a living individual in real-time

Requires a protocol-specific Informed Consent

The front-door consent does not apply to these studies

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Retrospective Data Reviews

Use existing medical information

Can include radiology films

Requires Waiver of Informed Consent and Waiver of Authorization to Use/Disclose PHI

• Research conducted in an educational setting and involves normal education practices

• Research involves educational tests, surveys, interviews or observation of public behavior

Exempt Research

• Research involves collection or study of existingdata, documents, records

Your research may be eligible for exemption,but you are still required to submit it

to the IRB for approval

What is a Case Report?

Data is listed and/or described separately

How do you know whether a small case report or series should be submitted?

Data is listed and/or described separately for EACH subject

No aggregated data compiled

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Case Report Guidelines

IRB approval not required

Considered to be educational

Still subject to HIPAA rules

Cell Lines & Deceased Subjects

Research using commercially available cell lines DOES NOT require IRB review.

Research using samples from deceased subjects usually does not require IRB approval.

If you are in doubt, send a brief memo to the IRB with supporting documents prior to the research being performed. An IRB Chair and/or designee will review the submission to determine if a protocol is required.

Contact InformationOPR Physical Address

Pickens Academic Tower (PAT)1400 Pressler St, Suite 8.600, Unit 1437

OPR Office Main Line713-792-2933

IRB Office E-mail [email protected]

Rachel Avants713-563-2496

[email protected]

1

Overview of Adverse Events


Office of Research Education and Regulatory Management July 2009

Objectives

Define: adverse events (AEs)serious adverse events (SAEs)expected / unexpected events

2

expected / unexpected events

Determine: attribution of event

Understand: timelines for following and reporting SAEs

Adverse Event Definition

Any event that is unfavorable or unintended that occurs after the administration of a drug, biologic, or

3

administration of a drug, biologic, or device regardless of whether it is considered related to the medical treatment or procedure.

• Worse than baseline• Importance of baseline assessment

2

Terms used for “AE”Adverse Experience (AE)

Adverse Drug Reaction (ADR)

Adverse Drug Experience/Event (ADE)

4

Adverse Reaction (AR)

Adverse Device Effect (ADE)

Side Effect (SE)

Safety Information

Toxicity

Why is all of this

5

of this information important?

Consequences

• Protocol violations• Protocol closed by IRB

6

• Protocol put on hold by FDA• Protocol closed by sponsor• Research priviledges revoked

3


• Patient level of risk?

7

• Significant protocol toxicity?• Study continuation?• Protocol review interval?


• Analyzes risks/benefits

8

• Updates Investigator brochure• Informs federal regulatory agencies• Ammends package labeling

Key elements of AEs

1. Grade2. Attribution

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3. Expected/unexpected


4

1. Grade / Severity

• Numerical value between 1 and 5

10

• Number assigned by referencing a grading criteria

• NCI CTCAE version 3.0

2. Attribution

• Aka “relationship” or “causality” or “drug related assessment”

• A determination made by a clinical

11

A determination made by a clinical investigator that describes the relationship or association of the study product with an adverse experience

• Note: At MDACC, this responsibility cannot be delegated to research staff

MDACC/NCI categories of attributions

• Unrelated - is clearly not related to study agent

• Unlikely related is doubtfully related to study agent

12

• Unlikely related - is doubtfully related to study agent

• Possibly related – may be related to study agent

• Probably related – is likely related to study agent

• Definitely related – is clearly related to study agent

5


• Is it a known side effect that can occur with the use of the drug?

13

• Is there another explanation for the adverse experience?

• What is the timing of events or is timing appropriate for the event?


• What are the drug levels?

14

• What happened to the adverse experience when the drug was decreased or stopped?

• What happened when you rechallenged the patient with the drug?

3. Types of Adverse Events• ________________ Events **“known” eventslisted in drug information

15

• ________________ Events **“unknown” eventsnot listed in drug information

** not a patient assessment;only based on drug information

6

Recording

• Review protocol for requirements• AE data may be received in numerous

ways from various sources

16

y• AE data may be collected by many

different employees

• Organization, communication, and timing is key!

Recording tips• Always need start and stop date of AE

• Timing: last dose?

17

last dose? when notified?

• Interventions: dose modified or stopped? patient withdrawn?medication / medical interventions needed?

Reporting Adverse Events

• ________________ reportingDescribe events in write up of protocol findings usually at study

18

protocol findings-usually at study end or interim analysis.

• ________________ reportingImmediate reporting of events to specified individuals, committees or agencies.

7

Clarificationof SAE

19

of SAE Terms and Definitions

Terms used for “SAE”

• CFR - Serious Adverse Drug Experience (SAE)

20

• CFR Proposed – Serious Suspected Adverse Drug Reaction (SADR)

• ICH – Serious Adverse Event (SAE) or SeriousAdverse Drug Reaction (Serious ADR)

• NCI – Adverse Event

SAE Definition(based on one of the outcomes listed below, not a certain grade

or attribution)

Any adverse drug experience occurring at any dose that results in any of the following outcomes:

21

1. Death2. Is life threatening3. Requires inpatient hospitalization or

prolongation of existing hospitalization4. Persistent or significant disability or

incapacity5. Congenital anomaly / birth defect

• Other important medical event

8

Terms as related to SAEs

• Expected versus unexpected• Life threatening

22

• Expedited versus routine• Initial versus follow-up• “Other”

SAE Categories

“Expected versus “Unexpected”“Internal” versus “External”

23

Internal versus External

• Affects type of reporting required• Affects type of form used• Affects who receives report

___________ SAE Events

• SAEs that occur at the MD Anderson (MDACC) site

24

• Affects all patients enrolled on MDACC protocols

• Includes patients enrolled here, but receiving part of their care elsewhere

9

_____________ SAE Events• SAEs that are reported to the PI through the

sponsor, because an unexpected SAE that has been determined to be related to the drug has occurred at another site with the

t d d

25

same study drug

• May not be same protocol or use for drug, but only same agent being used

• “Other site” can also mean another MDACC investigator / department

Reporting by PI

For internal SAEs:Always:• By PI to IRB• By PI to Sponsor (if there is one)

26

Sometimes:• By PI to MDACC (ORE&RM)• By PI to Manufacturer

For external SAEs:• Always by PI to IRB (from info received

from study sponsor)

Reporting by Sponsor

For internal SAEs:Always:• To FDA

27

Sometimes:• To IBC (Institutional Biosafety Committee)• To RAC at NIH

(Recombinant DNA Advisory Committee at National Institutes of Health)

For external SAEs:• Always: To other sites

10

Research demands involvement.It cannot be delegated very far

28

It cannot be delegated very far.Anonymous

Minimum Reporting Timeframes at MDACC

• Usually 24 hours for reportable deaths **

29

• 5 working days for all other reportable SAEs **

** Days are counted from date of knowledge of the event

Reporting SAEs

30 Day Rule

30

All reportable events that occur within 30 days of receiving last dose of study drug must be reported according to guidelines

11

Which guidelines to use?

Follow most stringent guidelines for your individual protocol

31

1. Protocol and/or appendices2. Sponsor requirements3. MDACC / IRB Guidelines4. Code of Federal Regulations

Patient

Research Nurse, PI,Data Manager

Cycle of reporting of event

32

Data Manager

IRB Sponsor

All sitesFDA

Forms for SAE Reporting

• Sponsor Forms• IRB Forms and logs (available on-line or from IRB)

33

(available on line or from IRB)• On-line reporting

Watch for inaccuracies, missing key data, discrepancies, and incorrect information

12

Key elements of AEs

1. ___________2. ___________

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3. ___________/____________


References

• On-line alphabetical index

35

• Computerized “safety profiler”• On-line references• MDACC Phone contacts

Alphabetical Indexhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcae_index.pdf

36

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Computerized Programhttp://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx

37

On-line References

• MDACC IRB (Human Subjects Manual)• For MDACC IND Studies-SOPs at Intranet site: Investigational New Drug (IND) Office

• Regsource.com-see “Code of Federal

38

gRegulations” 21 CFR § 312.32 - INDsafety reports, definitions

• FDA-www.fda.gov• NCI- http://ctep.info.nih.gov• ICH-www.ich.org• Sponsor’s website

Institutional References• MDACC IRB Help line: 792-2933 or “IRB help” in Lotus Notes

Human Subjects Manual On-Line – forms, logs and guidelinesGeneral questions and questions re: log Mira Shah 563-5437

• Submit External SAEs to Mary Fields 563-5441• Submit Internal SAEs to Rosa Jaramillo 563-5443

• For studies with Pharmaceutical Sponsors:

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Study monitor, protocol contractSponsor’s written guidelines for CRFs, SAE reporting

• NCI Studieswww. cancer.gov-printable copy of CTC criteria and alphab. indexSylvie Marcy 563-5456

• For MDACC IND StudiesORERM SOPs for IND Studies – Intranet site under: “Investigational New Drug (IND) Office”Study monitor, or Gloria Morris 563-0379

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Thank you!


Office of Research Education and Regulatory Management [email protected]

713-563-0379


University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious Adverse Events

PURPOSE It is the policy of The University of Texas M.D. Anderson Cancer Center

Institutional Review Board system (UTMDACC IRB) to comply with the regulations governing human subjects’ research.

POLICY STATEMENT

The purpose of this policy is to protect human subjects’ safety by mandating that investigators report adverse events, involving risks to subjects and others, to the UTMDACC IRB system. The UTMDACC IRBs review and act on reports of adverse events to determine:

• if the risk-benefit ratio continues to be acceptable; • if the research protocol and informed consent document accurately

and completely presents the risk information to research subjects; • if subjects already enrolled should be advised of newly identified

risks and/or be re-consented. SCOPE This policy applies to all clinical trials conducted at UTMDACC involving

investigational new drugs, commercially available drugs, biologic products, devices, behavioral science, laboratory and chart reviews.

DEFINITIONS Adverse Event (AE) – 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. For minimal risk studies such as behavioral science, laboratory, and epidemiologic protocols, as well as chart reviews, reasonable judgment must be used to determine what constitutes an AE. Expected AE - Any AE with specificity or severity that is consistent with the current Investigator Brochure (IB) or consistent with the risk information described in the Informed Consent Document (ICD) or general investigational plan. All clinical protocols should include a list of the expected and anticipated events or hospitalizations relating to the study treatment. Unexpected (Unanticipated) AE - Any AE, with specificity or severity that is not consistent with the current IB or not consistent with the risk information described in the ICD or general investigational plan.


Serious Adverse Event (SAE) – Any AE associated with the subject’s participation in research that:

• results in death; • is life-threatening, (places the subject at immediate risk of death

from the event as it occurred); • results in inpatient hospitalization or prolongation of existing

hospitalization; • results in persistent or significant disability/incapacity; • results in a congenital anomaly/birth defect; or • based upon appropriate medical judgment, may jeopardize the

subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Internal AE - An AE occurring in a subject who is enrolled in a protocol or study that is under the oversight of a UTMDACC IRB. External AE – An AE occurring in a subject who is not enrolled in a UTMDACC protocol or is on a protocol at a site that is under the oversight of another IRB. Generally, the PI has received notification of this AE from the protocol sponsor. Example: Medwatch report, CIOMS report, Safety reports. Related: Events directly or indirectly attributed to study drug, device or procedures and/or study participation. Events occurring with sufficient frequency to suggest that they are not random. Unrelated: Events that would occur regardless of study participation, including events that are clearly random occurrences. If the frequency of the event suggests a possible connection to the study intervention, then it should be considered related. AE Attribution - The determination of whether an AE is related to the research (medical treatment or intervention): Definite – It is clearly related Probable - It is likely related Possible - It may be related Unlikely - It is doubtfully related Unrelated - It is clearly NOT related AE Severity - Refers to the intensity (grading) of a specific AE. All clinical trials conducted at UTMDACC must use the “CTCAE v3.0 grading scale” for AE documentation and reporting (Publish date June 10, 2003). For the purpose of this policy, toxicity is synonymous with AE.


Minimal Risk - Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of a routine physical examination, physiological examination or laboratory testing. Designation of minimal risk will be determined by the IRB at the time of initial approval and reviewed at least annually during continuing review.

Multicenter Studies Since UTMDACC PIs participating in multicenter trials are unable to prepare a meaningful summary of SAEs, at the time of continuing review they should submit the current report from the monitoring entity (e.g. research sponsor, coordinating statistical centre, or DSMB/DMC). The report should include the following:

• a statement as to what information was reviewed by the monitoring entity (e.g. study-wide AEs, interim findings, recent literature relevant to the research);

• date of the review; • monitoring entity’s assessment of the information. Information that

is considered inadequate by the PI should be returned to the monitoring agency/sponsor for completion.

Institutional Procedures

Reporting Requirements for Internal AEs

Serious Internal AEs (SIAEs) requiring prompt reporting to the IRB All internal AEs that include all of the following will require prompt reporting to IRB via the Office of Protocol Research (OPR):

• Serious • Unexpected • Related (definitely, probably, or possibly related) to participation in

the research. Timeline for prompt reporting: 1. Within 1 working day (24 hours) from the time the research team

becomes aware of the event = Deaths that are unexpected and definitely, probably or possibly related to study intervention that occur during and within 30 days after the last day of active study intervention.



SAEs will require prompt reporting from the time protocol specific consent is signed, and screening has begun, during the course of study intervention and within 30 days after the last day of active study intervention. Beyond 30 days of study intervention, completion of only those SAEs that, in the judgment of the investigator, are related to research will require prompt reporting.


SIAEs Requiring Documentation on AE Log: All SIAEs that do not fall under the prompt reporting requirements should be reported during continuing review using the Internal SAE Log or database printout. Note: If a trend or recurring adverse events are seen, the PI should report these events using the Internal SAE report Form for prompt reporting. Individual reports submitted to IRB that do not meet the requirements for prompt reporting will be returned to PI.


Reporting Requirements for External AEs

Serious External AEs (SEAEs)Requiring prompt Reporting to IRB ONLY those external AEs that include all of the following will require prompt reporting to the IRB via OPR

• serious, • unexpected, • related (definitely, probably, or possibly related)

Reporting Timeline for prompt reporting: 1. Within 5 working days from the time the research team becomes

aware of the event = Unexpected deaths that are attributed by the Sponsor as definitely, probably or possibly related to study intervention that occur during and within 30 days after the last day of active study intervention.



SEAEs are required to be reported to the IRB beginning on the date of the UTMDACC IRB approval letter of the associated protocol. EAEs Requiring reporting to IRB using External AE Log: All SEAE that do not fall under the prompt reporting requirements should be reported using the External SAE Log or database printout or summarized and submitted during continuing review. Individual reports submitted to IRB that do not meet the requirements


for prompt reporting will be returned to PI.


This policy does not replace the reporting requirements to the FDA, the sponsor or monitoring agency.

Reporting Requirements for trials involving minimal risk

Reporting for trials involving minimal risk For protocols designated as minimal risk, AEs considered serious, unexpected and definitely, probably or possibly related to the study must be reported promptly as described above. [AEs considered to be unrelated to the study and non-serious AEs must be reported during continuing review (annual report)].

Reporting of SAEs for Terminated Protocols

Reporting of SAEs for Terminated Protocols Only those serious AEs that were unexpected and may impact the health, welfare or safety of subjects must be reported. For example, submit reports of secondary malignancies or problems with implanted devices.

Forms A written report will be submitted to the UTMDACC IRB using one of the

following forms: Internal SAE Report Form for Prompt Reporting: The Internal SAE Form should be utilized to report events that occur to subjects enrolled on a UTMDACC protocol/study. Internal SAE Addendum Form for Prompt Reporting: May be completed if the protocol sponsor requires a protocol specific form to be completed for subjects enrolled on a UTMDACC protocol/study, i.e., Medwatch report, CIOMS report. This addendum should be completed and attached to the sponsor form for submission. Departmental External SAE Report Form for Prompt Reporting: External SAEs of single or multiple protocols using the same drug, within a department can be submitted using the Departmental External AE Form for Prompt Reporting. Internal SAE Log All AEs not requiring prompt reporting to the IRB have to be listed on this log or a database print out with the same information can be submitted during continuing review. External SAE Log All AEs not requiring prompt reporting to the IRB have to be listed on this log or a database print out with the same information can be submitted during continuing review.


Safety Summary Report Submission Memo All external safety summary reports/alerts containing multiple AEs that briefly describe each event as updates received from the sponsors must be submitted using the safety report submission memo.

Form Completion

1. All the forms must be completed in full. 2. Protocol status must have only one choice. 3. If the SAE is noted as “ongoing” at the time of initial reporting, a follow-

up report will be required when the outcome of the SAE is known or when the event is considered to be permanent.

4. For follow-up reports, the date that the research team is notified should be the same as that of the initial report and the date submitted should be the actual date the follow-up report is submitted.

5. A concise synopsis describing the event must be provided. For follow-up reports, an updated synopsis must be provided.

6. If a report is being submitted outside of the stated time frames in this policy, a justification must be provided. (Note: failure to report an SAE in time may be considered a violation and repeated occurrences may constitute “continuing non-compliance”)

7. For reasons of confidentiality, subject names must NOT be included in any report or must be blacked out on patient reports. Subject identifiers such as patient ID or accession numbers should be used instead.

8. All report forms must include the attribution of the event. 9. The report form must be signed by the PI. The form can be signed by

the attending physician, but only when the PI is not available. All forms are located in the Human Subject Research Manual under Chapter 15.

REFERENCE: 21 CFR 56.108(b) 45 CFR 46.103 21 CFR 310.305 45 CFR 46.109 21 CFR 312.32 45 CFR 46.111 21 CFR 314.80 45 CFR 46.113 OHRP and HSS Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 25, 2007 Committee Review Committee: Names: Date: Institutional Review Board 3 Richard L. Theriault, D.O.

Ralph S. Freedman, M.D. Linda S. Elting, Dr. Ph.

November 1, 2006

Committee: Names: Date: Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. March 26, 2008 Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. April 23, 2008 Institutional Review Board 3 Ralph Freedman, M.D., Ph.D. March 25, 2009