Download Adverse Event Reporting Requirements

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SCHEMA
Table of Contents
1.
Introduction ............................................................................................................................. 5
2.
Objectives ................................................................................................................................ 5
2.1
Primary Objectives ........................................................................................................... 5
2.2
Secondary Objectives ....................................................................................................... 5
3.
Eligibility Criteria .................................................................................................................... 5
3.1
Inclusion Criteria .............................................................................................................. 5
3.2
Exclusion Criteria............................................................................................................. 6
4.
Registration Procedure ............................................................................................................ 6
4.1
5.
Registration and/or Randomization.................................................................................. 6
Treatment Plan or Research Design ........................................................................................ 6
5.1
Administration Schedule .................................................................................................. 7
5.2
Dose Modification ............................................................................................................ 7
5.3
Duration of Therapy ......................................................................................................... 7
5.4
Other ................................................................................................................................. 7
5.5
Data Safety Monitoring Plan ............................................................................................ 7
6.
Measurement of Effect ............................................................................................................ 7
7.
Study Parameters ..................................................................................................................... 7
8.
Drug Formulation and Procurement ........................................................................................ 8
8.1
Drug Descriptions (known toxicities and formula when available) ................................. 8
8.2
Means of Supply............................................................................................................... 8
8.3
Storage Methods ............................................................................................................... 8
8.4
Procurement Methods ...................................................................................................... 8
9.
Data and Safety Monitoring Plan ............................................................................................ 8
9.1
10.
Protocol Monitoring Guidelines ....................................................................................... 9
Adverse Event Reporting Requirements .............................................................................. 9
10.1
Definitions .................................................................................................................... 9
10.2
Adverse Event Reporting Procedures ......................................................................... 11
10.3
Serious Adverse Event Reporting Procedures ............................................................ 12
10.4
FDA Reporting Procedures (312.32 info/include annual reporting for INDs) .......... 12
10.5
Multi-center Clinical Trials Reporting Procedures .................................................... 12
11.
Statistical Considerations ................................................................................................... 12
12.
Data Considerations and Regulatory Obligations .............................................................. 14
12.1
Adherence to Regulations and Peer Review............................................................... 14
12.2
Data and Records Storage/Retention .......................................................................... 14
13.
References .......................................................................................................................... 15
Introduction
The Introduction should give the background and rationale for initiating the trial. Pre-clinical
and clinical data should be quoted in detail. The implications for future clinical trials should be
stated.
For investigator-initiated studies, a paragraph describing gender and minority
participation should be included at the end of this section. Sample language is as follows:
{It is the policy of the Mary Babb Randolph Cancer Center to strive for gender and minority
patient participation that represents the population of West Virginia in all clinical investigations.
Between January 2012 and December 2012, 192 patients were enrolled onto clinical trials at the
Mary Babb Randolph Cancer Center. Of these patients 52 percent were female and 1 percent
were members of minority ethnic groups. It is anticipated that a similar or greater proportion of
patients on this study will be female and/or members of ethnic minorities. It is important to
recognize that according to the 2011 US Census Bureau (available at
http://quickfacts.census.gov) that the State of West Virginia minority ethnic group (e.g., not
limited to African American and Hispanic)population is 3.5% Black (national average 13.1%)
and 1.3% Hispanic (national average 16.7%). The majority of Black West Virginians live in the
southern part of the state and MacDowell County is the only county in WV whose Black
population approaches the national average.}
Objectives
This is the key section for any clinical trial. The investigator should clearly state each objective
for the proposed trial.
2.1
Primary Objectives
2.2
Secondary Objectives
Eligibility Criteria
State the specific criteria for eligibility
3.1 Inclusion Criteria
(Examples include but not limited to the following; revise per clinical trial requirements)
3.1.1 Histologically confirmed cancer, residual, recurrent or metastatic
3.1.2 Adequate hepatic, renal and bone marrow function
3.1.3 Informed consent
3.1.4 Patient must have measurable or evaluable lesion (depending on the clinical trial)
3.1.5 Patient must be inoperable with no other definitive therapy available
3.2 Exclusion Criteria
(Examples include but not limited to the following; revise per clinical trial requirements)
3.2.1 Prior therapy with drugs to be used in the proposed clinical trial
3.2.2 Disease process which might be adversely affected by a particular drug such as
congestive heart failure/Adriamycin
3.2.3 Patients with acute intercurrent complications such as an infection or post surgical
complications
3.2.4 Patients below a certain age or with a poor performance status such as ECOG 3 or 4
3.2.5 Patients with a history of second malignancy
Registration Procedure
4.1 Registration and/or Randomization
This section outlines the method of registration and/or randomization as carried out by the
Clinical Trials Research Unit (CTRU). The guidelines will be developed for an individual study.
For example, if the trial involves a randomization, then details of stratification such as
anatomical extent of disease, prior therapy, histological subtype, and performance status, etc.
will be specified. If the trial is Phase II or Phase I then the procedure for registration with the
CTRU will be detailed.
Treatment Plan or Research Design
This section will vary depending on the nature of the clinical trial. The following examples are
given for a drug treatment program.
5.1
Administration Schedule
5.1.1 Description of various treatments including dose and schedule of all drugs used.
5.2
Dose Modification
5.3
Duration of Therapy
5.3.1 Define criteria for stopping therapy. For example, disease progression or
experience of unacceptable drug toxicity.
5.3.2 Define duration of therapy for patients with static disease
5.3.3 Define duration with response and what will be done with responders after specific
dose of drug with organ-limiting toxicity
5.4 Other
Where applicable consider recommendations for antiemetic therapy, guidelines for use of
radiation therapy for pain or life threatening tumor progression…
5.5
Data Safety Monitoring Plan
5.5.1 Suggested text is as follows (include the MBRCC DSMP as per level of risk and any
specific monitoring requirements per the MBRCC Protocol Review and Monitoring
Committee)
“This protocol will adhere to the policies of the Mary Babb Randolph Cancer
Center Data and Safety Monitoring Plan, guidelines in accordance with NCI
regulations. The Data Safety and Toxicity Committee (DSTC) will review all
serious adverse events and toxicity reports as well as continuing reviews.”
Measurement of Effect
In this section the parameters for assessing the effect of an intervention are defined. Each
protocol will specifically define these endpoints. For example, complete response, partial
response, no change, and progressive disease will be defined using criteria for drug treatment
trials. The extent of restaging that is required to document a complete response must be defined.
The protocol should state who will review the clinical data, e.g., will the PI review all responses
or will a delegated review committee evaluate response data, RECIST criteria should be used for
solid tumor response assessment.
Study Parameters
Study parameters are best presented in a table form with parameter and indicated time for
evaluation. For example (please create a protocol-specific table):
Parameters__________________________________________________________________
Every 3 months
Prior to Therapy
History and Physical Exam
Measurement of Tumor
Performance Status
Hemoglobin and HCT, WBC w/ diff,
platelet count, BUN, serum
creatinine, glucose, bilirubin,
alkaline phosphatase, SGOT
Weekly
Before each Drug administration
The following guidelines should be used for parameters in advanced disease protocols:
a) All scans and x-rays should be obtained within 4 weeks of the planned initiation of
treatment.
b) Scans or x-rays used to document indicator lesions for measurable or evaluable
disease shall be done within 2 weeks of initiation of treatment.
c) CBC with differential, liver function studies and chemistries shall be done within one
week of initiation of treatment protocol.
Drug Formulation and Procurement
8.1
Drug Descriptions (known toxicities and formula when available)
8.2
Means of Supply
8.3
Storage Methods
8.4
Procurement Methods
Data and Safety Monitoring Plan
This protocol will adhere to the policies of the Mary Babb Randolph Cancer Center Data and
Safety Monitoring Plan (DSMP), guidelines in accordance with NCI regulations. The DSMP for
each protocol is continuously monitored for patient safety, to ensure the veracity of the data, and
effective implementation.
The Clinical Trials Working Group (CTWG) is an executive committee composed of MBRCC
leaders which provide administrative oversight of clinical research conducted at the MBRCC.
The Protocol Review and Monitoring Committee (PRMC) is responsible for reviewing all new
clinical trials; whereas the Data Safety and Toxicity Committee (DSTC) is responsible for the
safety, validity of data, toxicity and response reporting and monitoring of MBRCC clinical
research.
9.1 Protocol Monitoring Guidelines
Please choose the applicable section below based on the PRMC-assigned risk level:
High Risk – A trial may be considered high risk based on novelty of therapeutic intervention or
the degree of risk to the patient. Examples include but are not limited to the following:
investigator-initiated Phase I trials, first in human trials, gene therapy or any study involving
drugs with potentially severe and/or life threatening side-effects (e.g., stem cell therapies).
Investigators and the Clinical Trials Research Unit (CTRU) staff will conduct continuous review
of data and patient safety with the designated Patient Protocol Review Committee (as listed in
Section B above) at their weekly meeting. The status and results of each patient’s treatment are
discussed and documented in the minutes. The discussion will include for each dose level: the
number of patients, significant toxicities as described in the protocol, dose adjustments, and
responses observed.
Monthly summaries will be submitted to the DSTC for review.
Moderate Risk – A moderate risk trial may include an agent with less novelty for which there is
some clinical experience and appreciation of clinical toxicity. Examples include but are not
limited to: Phase I, Phase II, or Phase III trials that involve an agent that has moderate toxicity.
Quarterly summaries will be submitted to the DSTC for review.
Low Risk – A low-risk trial typically include agents for which the clinical safety spectrum is
generally well characterized or other non-interventional types of studies. Examples include but
are not limited to: Phase III trials with existing extensive safety data, registries, correlative trials,
behavioral health, prevention, etc.
Annual summaries are reviewed coinciding with the WVU IRB Continuing Review schedule.
The DSTC will review all major protocol violations and SAE’s requiring expedited reporting, as
defined in the protocol. Periodic reporting to the DSTC should include summary data regarding
enrollment, patient status, and safety and toxicity as defined in DSMP Reporting Requirements.
Adverse Event Reporting Requirements
If applicable: There are no investigational devices or therapies and therefore adverse event
reporting is not necessary. However, this protocol will follow the WVU IRB reporting
requirements for unanticipated problems involving risks to subjects or others (UPIRTSOs).
10.1 Definitions
The following are definitions of adverse events as defined by 21CFR312.32.
10.1.1 Types of Adverse Events
Adverse Event means any untoward medical occurrence associated with the use of a drug
in humans, whether or not consider drug related.
Life-threatening adverse event or life-threatening suspected adverse reaction: An
adverse event or suspected adverse reaction is considered “life-threatening” if, in the view
of either the investigator or sponsor, its occurrence places the patient or subject at
immediate risk of death. It does not include an adverse event or suspected adverse reaction
that, had it occurred in a more severe form, might have caused death.
Serious adverse event or serious suspected adverse reaction: An adverse event or
suspected adverse reaction is considered “serious” if, in the view of the investigator or
sponsor, it results in any of the following outcomes:





Death,
A life-threatening prolongation of existing hospitalization,
A persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions, or
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require medical or
surgical intervention to prevent of the outcomes listed above.
Suspected adverse reaction means any adverse event for which there is a reasonable
possibility that the drug caused the adverse event. “Reasonable possibility” means there is
evidence to suggest a causal relationship between the drug and the adverse event.
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse
reaction, which means any adverse event caused by a drug.
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event
or suspected adverse reaction is considered “unexpected” if it is not listed in the
investigator brochure or is not listed at the specificity or severity that has been observed;
or, if an investigator brochure is not required or available, it is not consistent with the risk
information currently described.
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned
in the investigator brochure as occurring with a class of drugs or as anticipated from the
pharmacological properties of the drug, but are not specifically mentioned as occurring
with the particular drug under investigation.
10.1.2 Adverse Event Grading
Grade
0
Description
No AE (or within normal limits).
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention (e.g., packing cautery)
indicated; limiting age-appropriate instrumental activities of daily living (ADL).
3
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting
self-care ADL.
4
Life-threatening consequences; urgent intervention indicated.
5
Death related to AE
10.1.3 Adverse Event Attribution
Relationship
Unrelated to
investigational
agent/intervention
Attribution
Unrelated
Related to
investigational
agent/intervention
Possible
Probable
Unlikely
Definite
Description
The AE is clearly NOT related to the
intervention
The AE is doubtfully related to the
intervention
The AE may be related to the intervention
The AE is likely related to the
intervention
The AE is clearly related to the
intervention
10.2 Adverse Event Reporting Procedures
May need revised per sponsor or funding source – below is recommended text:
It is the responsibility of all investigators to assess AEs during the subject’s participation in the
study. Subjects will be followed for 30 days after treatment has stopped or until death,
whichever comes first. Each AE should be followed until resolution, stabilization, or until it has
been determined that the study treatment or participation is not the cause.
Adverse events that occur after the subject has signed the informed consent must be documented
in the study database/case report forms (OnCore or other PRMC approved database), subject’s
medical records, and as required per additional institutional standards. Source documentation
must be available to support all reported adverse events.
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or
judged relevant by the investigator, should be reported as an adverse event.
This protocol will use the NCI Common Terminology Criteria for Adverse Events (CTCAE)
version 4.0 available at http://ctep.cancer.gov for adverse event reporting.
10.3 Serious Adverse Event Reporting Procedures
Serious Adverse Events requiring expedited reporting – Reported within 24 hours
Serious Adverse Events (SAE) requiring expedited reporting within 24 hours will also be
reported to the Medical Director for Clinical Trials or DSTC Chair/Co-Chair, within one
business day. NCI ADEERS form or FDA Medwatch Form #3500 and/or any other
documentation should be submitted. Within 5 working days the initial report and all subsequent
SAE documentation that is available will be submitted to the DSTC. The DSTC will determine if
further action is required.
If the SAE occurs on a multiple-institutional clinical trial coordinated by WVU MBRCC, the
Network Coordinator will ensure that all participating sites are notified of the event and resulting
action within two working days of the determination.
Serious Adverse Event – Reported within 5 working Days
Serious Adverse Events requiring expedited reporting within 5 working days will also be sent to
the Patient Protocol Review Committee or DSTC. NCI ADEERS form or FDA Medwatch Form
#3500 and/or any other documentation available at that time will be reviewed by the DSTC to
determine if further action is required.
If the SAE occurs on a multiple-institutional clinical trial coordinated by the WVU MBRCC, the
Network Coordinator will ensure that all participating sites are notified of the event and resulting
action within one working day of the determination.
10.4 FDA Reporting Procedures (312.32 info/include annual reporting for INDs)
10.5 Multi-center Clinical Trials Reporting Procedures
Statistical Considerations
Each protocol should be discussed with the Biostatistics Core Facility and approved before
submission to the Protocol Review and Monitoring Committee. This section should address how
each objective will be assessed. The following issues shall be discussed: determination of
sample size, estimated duration of study, accrual goal, method of analyses, and criteria for
stopping trial.
Meaningful statistical design of clinical trials is facilitated if the statistician understands the
background of the disease being studied, such as its natural history as well as its history using
current treatments. The PI should provide (1) the endpoints of the study such as response rate,
toxicity, disease-free survival, or overall survival, and (2) patient characteristics that affect
response of the disease under consideration such as performance status, extent of disease, prior
therapy, metastatic sites, etc.
The PI and statistician should consider sources of patient accrual such as other centers and
'feeder' trials (i.e., ones with higher priority) available to determine expected accrual rates. The
disease or diseases being studied and ethical questions present in the treatment of these diseases
can influence the choice of experimental design such as single stage, multiple stage, or
crossover; therefore, a discussion between the PI and the statistician should include these
considerations as well.
More specific requirements can be broken down by the type of trial:
Phase I:
No particular additional requirements. Sample size is determined by results as
trial proceeds. A sample size of 25 patients is not unusual.
Phase II and III requirements:
A. The number of patients that can be accrued per year.
B. The percent of accrued patients usually evaluable.
C. Error Tolerance.
1. False positive error (recommending an ineffective agent for further study).
This error is conventionally 0.05.
2. 2.False negative error (declaring an effective agent ineffective). Typical
values are 0.10 or 0.20. As sample size increases, there is a decrease in this
type of error.
D. One-sample design (i.e., no randomization into two or more treatment groups).
1. Is there a standard treatment with known response rate? If yes, what is the
proportion of response to the standard treatment?
2. What is the accuracy needed in estimating the proportion of response (i.e.,
0.30 + .05)?
3. Is there a threshold value of proportion responding above which the agent
being tested is deemed a good candidate for Phase III testing? If yes, what is
that proportion (i.e., 0.20 or 0.30)?
E. Two-sample design (i.e., randomization into two treatment groups).
1. If two success rates are to be compared, then
a. What is the success rate of the control?
b. What is the expected success rate of the test treatment?
2. If two survival distributions are to be compared (when substantial censoring
occurs), then
a. What is the median survival of the control groups?
b. What is the expected median survival of the treatment group?
c. Is the survival distribution approximately exponential?
Data Considerations and Regulatory Obligations
12.1 Adherence to Regulations and Peer Review
A statement that all institutional and NCI and federal regulations concerning patient consent
and peer judgment must be fulfilled. Sample language includes: “All international, institutional
(IRB), NCI, state, and federal regulations concerning informed consent and peer judgment will
be fulfilled.”
Include information/date on PRMC review.
12.2 Data and Records Storage/Retention
Particular attention should be given to the specification of which data elements should be
included in the Mary Babb Randolph Cancer Center Clinical Trials Research Unit OnCore
database.
Studies that are exempt from FDA oversight (sample records retention language): Because
this study is exempt from FDA oversight the study records will be kept per WVU CTRU standard
procedures. Upon study closure the records will be reviewed for completeness. All study
documentation will be stored in a secure location for up to seven years from the closure of the
study.
12.3 Informed Consent
Written informed consent must be obtained from the subject prior to study participation.
The informed consent document must be signed and dated by the subject and properly witnessed
(if applicable) before initiation of any study procedures including any change in medication or
initiation of study drug dosing.
Subjects must be consented in accordance with all local regulatory and legal requirements. This
process must include a verbal explanation of the nature, scope, and possible consequences of the
study provided in plain language. The information should be presented by the investigator
unless a designee is permitted by local regulations. The potential study subject should be
encouraged to ask questions about the study.
The informed consent document must be prepared in accordance with GCP guidelines and with
local regulatory and legal requirements. A copy of the signed consent form will be given to the
subject and the original document must be safely archived by the investigator so that the forms
can be retrieved at any time for monitoring, auditing, and inspection purposes.
The informed consent will be updated as appropriate (e.g., due to protocol amendment or if
significant new safety information that may be relevant to consent of the subjects becomes
available). If the informed consent is revised, it is the investigator’s responsibility to ensure that
an amended consent form is reviewed and signed by all subjects subsequently entered into the
study and those currently in the study.
Consent Form: It is recognized that consent forms will vary depending upon several factors,
including disease site and disease stage, intervention proposed, and WVU Institutional Review
Board. Investigators should refer to the policies and procedures of the WVU Institutional Review
Board at the following web site:
http://orc.research.wvu.edu/human_subjects_research_and_the_irb
The consent form should honestly express realistic expectations of participating in the research
study, avoiding inducement by raising false hopes. The following information should be
included in simple, non-technical lay terms; medical jargon should be avoided. It has been
suggested that a consent form should be written in a manner that is understandable to an
individual who has completed an eighth grade education.
IRB More than Minimal Risk Consent Form Template:
http://oric.research.wvu.edu/r/download/141977
IRB Only Minimal Risk Consent Form Template:
http://oric.research.wvu.edu/r/download/141976
References
List all publications referenced in this protocol.