Data Safety Monitoring Plans & Boards

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Last Modified: 10/11/03

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Procedure for Developing a Data and Safety Monitoring Plan

Questions regarding this document may be addressed to: Michele A. Carter, Ph.D. at mcarter@utmb.edu

Introduction
Background
Policy
Rationale
Definitions
Note
DSMP Template
Research Subject Advocacy Program
Appendix
Useful Websites

Approved by the Scientific Review Committee on 1/16/2002, Approved by the GCRC Advisory Committee on 5/16/02, Updated 10/08/02, Approved by the GCRC Advisory Committee on 10/17/02

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1.	Introduction:
	The GCRC places the highest priority on ensuring the safety of participants in clinical studies and the validity and integrity of data generated in the research process. The purpose of data and safety monitoring of ongoing studies is to ensure compliance with federal mandates, participant safety throughout the research process, and that the research remains scientifically and ethically justified.
2.	Background:
	The NIH policy for data and safety monitoring, initially published in 1998 and expanded in 2000, requires that all investigators who submit protocols for Phase I and Phase II trials include a detailed data and safety monitoring plan. Consistent with that requirement, the Advisory Committee to the Director of the NCRR has recommended that all GCRC protocols (not just clinical trials) have a Data and Safety Monitoring Plan (DSMP) that includes periodic review and reporting, as appropriate, for each study. A NCRR waiver allows a local GCRC Advisory Committee (GAC) to approve plans in lieu of the NCRR for Phase I and II clinical trials conducted on the GCRC but not funded by another NIH Institute. This approval is given following review of the study protocol by the UTMB IRB. Recommendations regarding the implementation of this requirement are found at http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp#VII.
3.	Policy:
	Effective immediately, all GCRC protocols must include a description of the DSMP, which will be submitted to the IRB and the GCRC GAC. All GCRC investigators will adhere to the Data and Safety Monitoring Guidelines detailed below. These guidelines augment the safety-monitoring requirements established by external oversight entities including the University of Texas Institutional Review Board (IRB), U.S. Department of Health and Human Services, Food and Drug Administration (FDA), and others as may be additionally required by some protocols. A description of the plan is required at the time of submission of the study protocol to the GCRC. The plan is a standard component of the Human Subjects Protection part of the application. The GCRC Scientific Advisory Committee and the IRB must approve the plan prior to enrollment of subjects in the study.
4.	Rationale:
	A DSMP is an individualized plan, written by the Principal Investigator (PI) responsible for the study. The DSMP sets forth mechanisms for reviewing and evaluating adverse events, toxicity, and other study-relevant data for investigator initiated clinical research studies at UTMB. The rationale for requiring a DSMP is the need to enhance research subject safety by clearly defining safety related issues prior to subjects being treated. These issues include:
4.1.	Monitoring the safety environment of research participants. Monitoring of the safety environment includes the safe handling of drugs, solutions, specimens, physical space and equipment. All GCRC protocols must specify the name of the individual responsible for monitoring the study progress and the safety of the participants, and the frequency with which a safety review of adverse events, protocol violations, dropouts or withdrawals, or interim data analysis will be performed. The DSMP should state that all key personnel involved with the study have completed training in the protection of human research participants mandated by the U.S. DHHS Office for Human Research Protections (OHRP). See: http://ohrp.osophs.dhhs.gov/
4.2.	Protecting the validity and integrity of the data collected for the study. Monitoring of data includes the quality of the consent process; the accuracy of the collection and processing of laboratory specimens; adherence to clinical study schedules; utility and efficiency of case report forms, databases, laboratory notebooks and/or medical progress records; and the maintenance of subject confidentiality. All GCRC protocols must have a documented plan for the collection, storage, protection, and analysis of research data. Plans should include a description of how the data is secured against inadvertent loss, the frequency with which the data is monitored to promote participant safety, and the measures employed to protect the privacy and confidentiality of the participants. Provisions for data storage sites and access must be defined. Data access should be limited to investigators and support personnel who need to enter and analyze data.
4.3.	Documenting, grading, attributing, and reporting of adverse events. Monitoring of adverse events is a regulatory requirement. All approved GCRC protocols must have a detailed plan for reporting unanticipated and serious adverse events as well as a plan for (minimum) annual reporting of all adverse events. Current federal regulations require ongoing monitoring of adverse events in order to ensure the safety of participants and the validity and integrity of the data. UTMB is required to follow written procedures to ensure prompt reporting to the IRB, institutional officials, and the department or agency head any “unanticipated problems involving risks to subjects or others” [45 CFR 46.103 (6) (5) (i)]. Unanticipated problems include the following: All suspected adverse medication reactions All reactions from medication overdose or withdrawal Apparently unrelated illnesses, including the worsening of a pre-existing illness Injury or accidents Abnormalities in physiological testing or physical examination findings that require clinical intervention or further investigation Laboratory abnormalities that require clinical intervention or further investigation, unless they are associated with an already reported clinical event
4.3.a	In addition, all Serious Adverse Events (SAE) require immediate reporting to the IRB, the Sponsor, FDA/NIH, and the GCRC. Serious adverse events are defined by regulatory criteria. The definition of an SAE is provided on Page 6. The NIH Web site detailing serious adverse events/effects is at: http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp#VIII. Although federal guidelines on DSMPs continue to evolve, the core elements of a DSMP should address the following points:
4.3.1.	The plan must be appropriate to an individual study’s objectives, design, and estimated risk level: The DSMP should specify the procedures employed to maximize participant safety throughout the study. Each plan should be tailored to fit the estimated degree of risk to the participant as well as the size and complexity of the study. Therefore, it is necessary to estimate the level of risk associated with the protocol, as this will drive the type of monitoring needed and the level of oversight required. In general, the risk assessment is performed by the IRB and may involve the following categories: Low risk: Studies of this risk level are limited to those that involve innocuous procedures but no therapeutic agent. These may include survey research, questionnaires, blood sampling, or observational studies on non-vulnerable adults. It is usually sufficient for the PI to monitor these studies and the plan should include a minimum of annual progress reporting to the IRB. Moderate risk: Studies of this risk level require a more detailed plan for patient safety monitoring and may include studies investigating a ‘safe’ therapeutic agent. These studies may require additional monitoring by a qualified medical monitor, safety officer, or an ad hoc safety committee. High risk: High risk studies include: clinical trials using investigational agents including some Phase I studies; some Phase II studies; all Phase III comparative clinical studies; multicenter studies coordinated by a UTMB investigator; investigator-initiated studies involving INDs, gene therapy studies, or other studies involving vulnerable subjects. These studies require a minimum of semi-annual reports plus additional monitoring measures as determined by the PI or IRB, which may include monitoring by a 3 member Data Safety Management Board, monitoring by a qualified medical monitor, or external oversight by an ad hoc safety committee.
4.3.2.	The Type and Frequency of Monitoring Needed: All PIs are required to report on the study status on an annual basis. The annual report will be submitted to the GCRC at the time of the required IRB continual review. There are several methods of data and safety monitoring that can be employed, depending on the level of risk: The plan should state who would be responsible for monitoring subject safety, protocol compliance, and adverse event reporting. Specific monitoring parameters may include subjects screened and enrolled, dropouts, primary and secondary efficacy endpoints, and/or the informed consent process. The following entities can monitor subject safety and protocol compliance: Principal Investigator -appropriate for investigator-initiated, single-site, nonrandomized studies of low risk, provided PI has no conflict of interest. External Monitor -a qualified individual not involved with the study, trained in monitoring. (i.e. safety officer, designated Medical Monitor) Data and Safety Monitoring Committee -appropriate for studies of high risk. The Scientific Review Committee or IRB may appoint a data and safety ad hoc committee. Data and Safety Monitoring Boards (DSMB) - Some Phase I, Phase II, and studies involving high-risk therapy and/or vulnerable subjects may require a DSMB. In many cases, Industry Sponsored/FDA Regulated Studies, Phase III, and higher risk Investigator-Initiated Studies require a DSMB. GCRC investigators conducting these and other high-risk studies must comply with the UTMB IRB Policy for Data and Safety Monitoring in Clinical Research (Appendix A-21 of the IRB Policy Manual).
4.3.3.	The plan must spell out how Adverse Events are documented, reported, graded, and attributed. Current federal regulations require ongoing oversight and monitoring of adverse events in order to ensure the safety of participants and the validity and integrity of data. A description of the plan for reporting non-serious anticipated and unanticipated adverse events as well as serious adverse events to the IRB, GCRC, funding and regulatory bodies, should be included in a DSMP.
4.3.3.a Documentation:	The plan should describe what the PI will do in the event of an adverse event while a subject is participating in the study and who will be responsible for monitoring adverse events. Should an Unanticipated and/or Serious Adverse Event occur, GCRC investigators must follow UTMB IRB requirements for Adverse Event reporting as well as those of the FDA or NIH. Any adverse event report submitted to the IRB, FDA or NIH will also be sent to the UTMB GCRC. If a patient safety issue of any nature should arise, the PI will notify the GCRC Program Director immediately to determine if a Data Safety Monitoring Committee should review the data. Any data analysis report, interim and/or final, which is sent to the IRB and/or FDA, will also be submitted to the GCRC.
4.3.3.b Reporting:	Clearly, any unanticipated problem involving “risk” that ultimately results in harm to the subject’s rights or well-being and that is related to a research intervention constitutes a reportable adverse event. At UTMB, all adverse events that are unanticipated and/or serious require reporting within 24 hours. All GCRC investigators must follow the UTMB IRB Adverse Event Policy available at http://research.utmb.edu/irb/irbm52_.doc. In addition, serious adverse events associated with GCRC protocols must be reported orally and in writing immediately by the PI (or monitor in his/her absence) to: Dr. Don W. Powell Interim Program Director of the GCRC Associate Dean for Research, School of Medicine Telephone: (409) 772-0752 The PI and/or the Data and Safety Monitoring Board will make an assessment of the relationship between the adverse event and the protocol/intervention for each adverse event occurrence. Investigators should follow the IRB terminology if available.
4.3.3.c Grading:	In addition to documenting and reporting adverse events, many regulations and sponsors require that adverse events be graded according to severity. The following scale grades adverse events by common features, and is often appropriate for use by GCRC investigators where such grading is indicated.
	UTMB GCRC Adverse Event (AE) Grading Scale:
	0= No Adverse Event or within normal limits 1= Mild Severity: Transient laboratory test alterations; discomforts noted but no disruption of daily activities; no therapy, or only symptomatic therapy required 2= Moderate Severity: Laboratory test alterations indicating injury without long-term risk; discomfort sufficient to modify normal daily activity; specific therapy required (i.e., more than symptomatic) 3= Serious Severity: Laboratory test indicating a serious health threat or permanent injury; incapacity, inability to work, inability to perform normal daily activity; hospitalization required or prolonged; emergency treatment required; life-threatening events; death
Note:	Investigators may use other grading scales such as the National Cancer Institute Common Toxicity Criteria, available at http://ctep.info.nih.gov.
4.3.3.d Attribution
	: In some cases it is necessary for the PI to provide a judgment as to whether the adverse event is associated with the medical treatment or with procedure. The following attribution scale is appropriate for use by GCRC investigators: Attribution Scale Unrelated Possible Probable Definite
5.	Definitions:
	An Adverse Event (AE): is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an experimental medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. An Adverse Event is any experience that has taken place during the course of a research project, which, in the opinion of the investigators, was harmful to a participant, increased the risk of harm, or had an unfavorable impact on the risk/benefit ratio of the study. Anticipated (Expected) Adverse Events: these are risks or events reported in the Investigator’s Brochure and listed in the consent form. The UTMB IRB and the GCRC will consider an adverse event as “anticipated” or “expected” only if it is discussed in the protocol and included in the Informed Consent document. Unanticipated (Unexpected) Adverse Events: an unanticipated adverse event is any unexpected untoward event or medical occurrence in a study subject that is not consistent with the known, predicted possible effects of the research protocol. An unanticipated adverse event can therefore be any unanticipated, unfavorable, and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study that was not listed in the protocol, consent form or investigator’s brochure. This includes any experience that suggests a significant hazard, contraindication, side effect, or precaution. In addition to this definition, the UTMB IRB and the GCRC interpret any adverse event not included in the Informed Consent document as a risk to be “unanticipated” or “unexpected.” [Adapted from HHS & FDA 21 CFR 312.62 (6), 21 CFR 50.27 (a), 21 CFR 312.32 (a), FDA Docket No. 93N-0181]. Serious Adverse Event (SAE): Serious adverse events are defined by regulatory criteria and include any of the following: Any hospital admission (unless hospitalization is preplanned) Unanticipated or life-threatening drug reaction including but not limited to one that necessitates discontinuation of study participation or that results in death Congenital anomaly occurring in the offspring of a research participant who had taken a study drug Exceeding the nature, severity, or frequency described in the investigator’s brochure or protocol Prolongs a stay in a health care facility Significant, persistent, or permanent harm or disability, either physical or psychological Death The NIH Web site detailing serious adverse events/effects is at: http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp#VIII.
	Data and Safety Monitoring Board (DSMB): DSMBs are typically committees of experts including scientists, physicians, statisticians, bioethicists, and others that perform ongoing monitoring of the data and safety of interventional research trials. A DSMB monitoring committee is required to determine safe and effective conduct of the research and to recommend conclusion of the trial when significant benefits or risks have developed, or if the trial is deemed unlikely to be concluded successfully. At each meeting, DSMBs review summary reports of adverse events, analyze interim data, cumulative toxicity summaries, reports of related studies, major proposed protocol amendments, data and monitoring plans/reports, safety and efficacy outcomes, and other aspects of protocol compliance. Following each meeting of the DSMB, the Principal Investigator should be provided with written information concerning findings or concerns related to the study. See UTMB IRB Policy on Data and Safety Monitoring as it pertains to DSMBs, available at: http://research.utmb.edu/irb/Manual3.docc.
6.	Note:
	Investigators submitting applications for NIH support of grants, cooperative agreements, or contracts after October 2000 should be aware that each specific Institute may have its own policies regarding data and safety monitoring. Institute data and safety monitoring policies that are known at this time include: NCCAM: http://nccam.nih.gov/research/policies/datasafety/ NCI: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm, http://www.nci.nih.gov/search/results.aspx NEI: http://www.nei.nih.gov/funding/policy/policy6.asp NHLBI: http://www.nhlbi.nih.gov/funding/policies/dsmb_est.htm, http://rover2.nhlbi.nih.gov/funding/policies/dsm-12.htm, http://rover2.nhlbi.nih.gov/funding/policies/dataqual.htm, http://www.nhlbi.nih.gov/funding/policies/dsmb_othr.htm NIA: http://www.nia.nih.gov/GrantsAndTraining/Policies/ImplementationPolicies.htm NIAID: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf NIAMS: http://www.niams.nih.gov/rtac/funding/grants/datasafe.htm NICHD: http://www.nichd.nih.gov/funding/policies/datasafety.cfm NIDA: http://www.nida.nih.gov/Funding/DSMBSOP.html NIDCR: http://www.nidcr.nih.gov/ClinicalTrials/ClincalTrialsProgram/GuidelinesDataSMCT.htm NIDDK: http://www.niddk.nih.gov/patient/patient.htm#policy NIMH: http://www.nimh.nih.gov/researchfunding/safetymonitoring.cfm NINDS: http://www.ninds.nih.gov/funding/ninds_patient_safety_guidelines.htm
	Data and Safety Monitoring Plan: (DSMP) Template
	Face Page: Identify number, personnel, contact information Brief Description of Study: May use protocol abstract Risk Assessment: Estimate risk level (low, medium, high) and briefly discuss risk consideration relevant to your protocol. Risk assessment should involve not only issues relating to potential risks and toxicities of study interventions, but also other risks, including risks associated with vulnerable populations (e.g., children, patients with dementia, UTMB employees), personal health information, privacy/confidentiality issues, problematic or difficult informed consent issues, and research in socially or politically sensitive areas (e.g., research involving minority populations, gene therapy research). Other factors that might be considered in a risk assessment include: risk inherent in the study population or the number/frequency of clinically adverse events in the absence of study interventions (as, for example, in a very medically ill study population), risks associated with the study interventions, previous experience with the study intervention, previous experience of the study PI, anticipated difficulties in meeting study goals (e.g., recruitment difficulties, drop outs from the study, noncompliance with the study protocol). Plan for Monitoring and Safety Review: Specify the name and contact information of the individual responsible for monitoring the safety environment of the participants (i.e. PI only, or additional monitoring by a Medical Monitor, Safety Officer, Independent Committee, or DSMB). Specify what you will monitor (i.e. subject eligibility, adherence to treatment plan, documentation of dropouts, evaluation of primary and secondary endpoints, adverse events, and/or problems with informed consent). If a DSMB is required, describe the composition of the board, what role the board will play, and the frequency of meetings. Confirm that the PI, IRB, RSA, and other appropriate entities will receive all reports of DSMB meetings and other aggregate data analyses that may be indicated in evaluating subject safety. Plan for Data Management: Indicate who is responsible for collection and storage of data, where it will be stored. (i.e. Lab notebook, CRF, database) and any security measures needed to properly protect data from inadvertent loss or inappropriate use. Include a description of how often interim data will be reviewed and by whom. Specify any conditions that would necessitate early termination of the study (i.e. some clinical trails require documentation of stopping rules that might be used if the participants are found to be exposed to excessive risks in relation to anticipated benefits). Indicate who will perform aggregate analysis of data and adverse events, if applicable. Plan for Adverse Event Reporting: Indicate the name and contact information of the individual responsible for monitoring and reporting the occurrence of adverse events throughout the study, whether they are anticipated, unanticipated, or serious, and the frequency of monitoring (annual, 6 months, other). Describe the anticipated adverse events listed in the Consent Form for this protocol. State your plan for how these will be reported and to whom (i.e. IRB, FDA, NIH). Identify the scale that will be used to grade the severity attribution of adverse events. You can use the GCRC Adverse Event Scales, available at http://www.utmb.edu/gcrc/aboutus/RSA/RSA.AE.htm#Grading Scale The Common Toxicity Criteria (CTC) scale available at: http://ctep.cancer.gov/. or another scale of your choice. Indicate that you will follow the UTMB IRB Adverse Event Policy on mandatory reporting of Serious Adverse Events (SAEs), and also report them immediately both orally and in writing to the GCRC Program Director or RSA within 24 hours of occurrence or recognition. http://research.utmb.edu/irb/irbm52_.doc Human Subject Training: Specify that all key research personnel have completed the NIH required Human Subjects Training
7.	Research Subject Advocacy Program:
	Research subject safety is an ethical and scientific obligation shared by all members of the research team, the sponsoring institutions, and the university community. Investigators and other key personnel may enhance safety by careful attention to the rights, interests, and welfare of research subjects at all phases of research. In a climate of heightened concern for research subject safety in clinical trials, the NIH has created a new position within the GCRC- the Research Subject Advocate (RSA). However, the role of the Research Subject Advocate in no way replaces or minimizes the primary roles held by the IRB and the PI for protecting human research participants, or the PI’s primary responsibility for detecting, documenting, and reporting adverse events. The main responsibility of the RSA is to ensure compliance with new NIH requirements regarding data and safety monitoring procedures, including the facilitation of reporting requirements for adverse events and ensuring the adequacy of the informed consent process. The UTMB GCRC Research Subject Advocate (RSA) is available to assist investigators, study coordinators, and nursing staff in all aspects of research ethics and reports directly to the Dean of the School of Medicine who is the Principal Investigator of the GCRC institutional grant. The RSA is responsible for the following in regard to data and safety monitoring: Assisting GCRC investigators in formulating data and safety monitoring plans. Providing recommendations regarding the adequacy of the data and safety monitoring plans of individual protocols to the GCRC Scientific Review Committee (SRC). Monitoring all ongoing GCRC studies for adherence to approved data and safety monitoring plans. Maintaining accurate records of the data and safety reports throughout the study. Safety reports may include, but are not limited to: Review of interim data analysis Cumulative adverse event summaries Recruitment and retention summaries Analysis of quality of data DSMB summary reports or minutes, if appropriate
8.	Appendix
	The GCRC Data and Safety Monitoring Policy has been developed to comply with the following federal policies and/or supporting regulations: The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 1979 DHHS The Common Rule 45 CFR 46.111 (a) (b), 1991 NIH/NCI Guidelines published as NIH Policy for Data and Safety Monitoring, June 10, 1998 Policy of the NCI for Data and Safety Monitoring of Clinical Trials, June 22, 1999 Further Guidance on a Data and Safety Monitoring Plan for Phase I and Phase II Trials, June 5, 2000 Essential Elements of a Data and Safety Monitoring Plan for Clinical Trials Funded by the NCI, April 2001 NCRR GCRC Recommendations on Patient Safety, June 2001 International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice Section 5.18 Notice of required education, June 5, 2000 UTMB Policy on the Protection of Human Subjects
9.	Useful Websites:
	NCI, June 10, 1998 Guidance on Data and Safety Monitoring: http://grants.nih.gov/grants/guide/notice-files/not98-084.html Further guidance on a DSMP, June 5, 2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html NCI’s Common Toxicity Criteria II (CTC II) available at: http://www.nci.nih.gov/search/results.aspx Further Guidance on the Safety Requirements for GCRCs: http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp Guidance on Adverse Event Reporting: http://grants.nih.gov/grants/guide/notice-files/not99-107.html UTMB IRB Adverse Event Policy, available at: http://research.utmb.edu/irb/irbm52_.doc Patient Safety Website: UTMB “Guidelines for Responding to an Adverse Event”: http://www.utmb.edu/patientsafety FDA: http://www.fda.gov/oc/oha Recombinant DNA molecules: http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html U.S. Department of Health and Human Services, Office for Human Research Protections (OHRP): http://ohrp.osophs.dhhs.gov/ Questions regarding this document may be addressed to: Michele A. Carter, Ph.D. at mcarter@utmb.edu Update 10/08/02