Human Research Protection Program Guidance Document. Data and Safety Monitoring Plans

Transcription

1 Overview Definitions Investigator Responsibilities Specific Elements of an Effective Data Safety Monitoring Plan (DSMP) When is a Data Safety Monitoring Board (DSMB) needed? How to create a Data Safety Monitoring Board (DSMB) Appendix: (DSMP) Templates Overview The IRB is responsible for determining if a study needs formal ongoing monitoring of data to ensure that research subjects will be protected. This responsibility stems from DHHS and FDA regulations, which list the following criterion for study approval: "when appropriate, the research plan makes adequate provisions for monitoring the data collected to ensure the safety of subjects" (45 CFR [a][6]). Definitions Data and Safety Monitoring Plan (DSMP) is a plan established to assure that each research study has a system in place for appropriate oversight and monitoring of the conduct and progress of the study that ensures: 1) important information that may affect the safety or welfare of participants comes to light and is acted upon as quickly as possible, and 2) the validity and integrity of the data. Data and Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) is a formal committee, independent of the trial organizers and investigator(s), that is specifically established to conduct interim monitoring, oversight and analysis of study information and data to assure the continuing safety of research participants, efficacy of the study intervention, appropriateness of the study, continued relevance of the study question, and integrity of the accumulating data throughout the life of a research project. DSMBs/DMCs are typically made up of individuals who have expertise in the field of investigation, experience in the proper conduct of clinical trials, and/or statistical knowledge, and who do not have any serious conflicts of interest (i.e., financial, intellectual, professional or regulatory). Investigator Responsibilities The Investigator is responsible for ensuring that there is an appropriate DSMP (with or without a DSMB, as needed) in place at the time of initial IRB approval and for ensuring that the safety-monitoring plan is implemented over the life of the protocol. Version: 7/22/13 Office of IRB 1

2 Elements of an Effective Data and Safety Monitoring Plan (DSMP) Note: A DSMP should be designed to be commensurate with the risks involved with the investigation. Most studies that qualify as minimal risk do not require a data and safety monitoring plan (a possible exception would be if the study involved a drug or device). The following is a detailed explanation of the elements that should be part of a Data and Safety Monitoring Plan: A. Identification of the individuals who will be responsible for monitoring the data, assuring protocol compliance, conducting the safety reviews, and determining the specified frequency of the review(s). 1. The PI should identify who is responsible for monitoring the study. a. Example: The principal investigator or named designee, e.g., sub-investigator, will monitor the data and conduct safety reviews, at a specified frequency appropriate to the level of risk. 2. The PI should specify the frequency of reviews in the DSMP. During the review process the principal investigator will evaluate whether the study should continue unchanged, require modification, or close to enrollment. a. Example: Data will be reviewed every 3 months. b. Example: Data will be reviewed after the first 5 subjects receive initial treatment and on a quarterly basis thereafter. 3. The PI should define the parameters within which, the data will be reviewed such as by time or per subject basis or any other specific and predetermined parameter or outcome as well as the procedure for analyzing the data such as the frequency of anticipated adverse events in treatment and control groups. The focus of the analysis is to determine whether enrollment should continue or be closed, whether the trial should continue as originally designed or require modification/amendment. 4. If applicable, stopping rules should be part of the Data and Safety Monitoring plan (if the study is a clinical trial of a medical intervention). It must be noted that the principal investigator, study sponsor, Data and Safety Monitoring Board (DSMB) or Committee (DSMC) (if one exists), the IRB, and other oversight committees, have the authority to stop or suspend the study or require modifications. B. Explicit Statement of Risk: The principal investigator must state the level of risk associated with participation in the study and must explain why that designation is appropriate. It is necessary to assess the risk associated with participating in a study in order to facilitate consideration of safety issues and to design a DSMP appropriate to the level of risk presented. Risks considered should include not only physical risks but also the possible harm to the subject(s) if confidential and sensitive data is inadvertently disclosed. Other considerations include whether vulnerable populations are included in the research study, if investigational agents or devices will be employed, the use of placebo in certain types of studies, and the underlying health of the study population(s). Version: 7/22/13 Office of IRB 2

3 C. Plan for Determining Relatedness of Adverse Events: The principal investigator is responsible for determining the likelihood that an adverse event is related to the study and must assess the relatedness. (See IRB Policy Reporting Adverse Events and Unanticipated Problems, and its associated Procedure.) A sample scale is provided below. Example: Attribution of adverse events: Definite: Adverse event is clearly related to investigational agent(s) or other study intervention(s) Probable: Adverse event is likely to be related to investigational agent(s) or other study intervention(s) Possible: Adverse event may be related to investigational agent(s) or other study intervention(s) Unlikely: Adverse event is likely not to be related to investigational agent(s) or other study intervention Unrelated: Adverse event is clearly not related to the investigational agents(s) or other study intervention(s) A scale for attributing adverse events other than that specified above may be used so long as the criteria are clearly defined and/or referenced in the DSMP (e.g., National Cancer Institute's Common Toxicity Criteria (CTC) See also OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events available at: and FDA Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs Improving Human Subjects Protection available at: D. Plan for Grading Adverse Events: The principal investigator must provide a plan for categorizing/grading adverse events using a scale similar to the one provided below. The plan should indicate what sorts of events would be included in each category. Example: Grades of Adverse Events: 1. Mild adverse event- discomfort noticed, but no disruption of normal daily activity 2. Moderate adverse event- discomfort sufficient to reduce or affect normal daily activity 3. Severe adverse event incapacitation, with inability to work or perform normal daily activity A scale for grading adverse events other than that specified above may be used so long as the criteria are clearly defined and/or referenced in the DSMP (e.g., National Cancer Institute's Common Toxicity Criteria (CTC), Serious Adverse Events: In addition to grading the adverse event, the PI must determine whether the adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it results in any of the following outcomes: death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other Adverse Event that, 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. Version: 7/22/13 Office of IRB 3

4 Examples of Adverse Events Reportable as Serious Adverse Events: Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse event that is rare in the absence of drug exposure. A series of adverse events that, on analysis, is both unanticipated and a problem for the study. The series of adverse events would be determined to represent a signal that the adverse events were not just isolated occurrences, and significantly affected the rights and welfare of subjects. An adverse event that is described or addressed in the investigator s brochure, protocol, or informed consent documents, or expected to occur in study subjects at an anticipated rate (e.g., expected progression of disease, occurrence of events consistent with background rate in subject population), but that occurs at a greater frequency or at greater severity than expected. Any other adverse event that would cause the sponsor to modify the investigator s brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to assure the protection of research subjects. E. Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse events occurring at a greater frequency than expected, and unanticipated problems involving risks to subjects or others to the IRB. The IRB requires reporting only for (a) serious AND unanticipated AND possibly, probably or definitely related adverse events and (b) anticipated adverse events occurring with a greater frequency than expected. The IRB also requires reporting for all unanticipated problems involving risks to subjects or others that are unexpected AND suggest that research participation places the subject or others at greater risk of harm than was previously known or recognized AND are related or possibly related to the subject s participation. Reports must be in writing and made in a timely manner (within 48 hours of the event) using the Reportable Event Form (as appropriate), which requires the investigator to assess the need for change to the protocol, the procedures or the consent document(s). For more information on the reporting of adverse events and unanticipated problems involving risks to subjects or others see HRPP Policy. F. Plan for reporting adverse events to co-investigators on the study, and as appropriate the protocol s research monitor(s), e.g., industrial sponsor, ), DSMBs, study sponsors, funding and regulatory agencies, and regulatory and decision-making bodies. Principal Investigators must review ALL adverse events. Principal Investigators must define plans for reporting and reviewing adverse events to fellow investigators and key study personnel, sponsors, research monitors and other oversight bodies. For Multicenter trials when NS-LIJ is the coordinating site, the NS-LIJ PI is responsible for reviewing safety reports forwarded by site investigators, sponsors or cooperative groups. As the PI assesses these reports, they should be categorized as serious or non-serious, and unanticipated or anticipated. Reporting of such to the IRB should be based upon HRPP Policy. Principal Investigators must define plans for reviewing and reporting non-serious, unanticipated and anticipated adverse events to fellow investigators, key study personnel and appropriate research monitors. Version: 7/22/13 Office of IRB 4

5 When is a Data and Safety Monitoring Board (DSMB) needed? The IRB may, in certain circumstances, require a DSMB, depending on the level of risk or if there is a potential for a significant conflict of interest on the part of an investigator that may adversely affects the design, conduct or reporting of the research. A DSMB does not replace a DSMP; it is simply an additional element of a DSMP When is a DSMB appropriate? In any study where the risk level is moderate to high. When a NS-LIJ Principal Investigator holds the IND/IDE for the investigational agent/device being used in the study. For Phase I and II trials if the studies have multiple clinical sites, are blinded, or employ particularly high-risk interventions or enroll vulnerable populations. When NS-LIJ is the coordinating site of a multicenter study. As a mechanism of managing a Conflict of Interest. When a NS-LIJ Principal Investigator or other key personnel is the inventor of an intervention being tested. When a NS-LIJ investigator has intellectual property rights to the agent(s)/device being tested. In general, Phase 3 Clinical Trials will have an independent DSMB. What are the attributes of a DSMB? When a DSMB is involved, the DSMB's organization, membership, responsibilities and operations should be described. Membership should include appropriate scientific and biostatistical expertise. The DSMB generally should be independent from the sponsor and investigator team. The degree of independence required depends on the risk level associated with the trial. The DSMB should be responsible for reviewing comprehensive, cumulative, unblinded safety reports, and employing stopping rules if there is evidence of differential effects in either risk or benefit. The descriptions of standard operating procedures should include frequency and documentation of periodic reviews, and submittal of written summary or minutes to the principal investigator. The investigator, upon receipt, must submit DSMB findings/recommendations to the IRB. When the NS-LIJ principal investigator is required by the IRB to constitute a DSMB, the following will likely be required: DSMB members do not have interests, financial or otherwise, in the outcome of the study. DSMB members who may be internal to NS-LIJ do not have reporting relationships to members of the research team. DSMB members who are internal to NS-LIJ are not members of the same department or section as the NS-LIJ principal investigator. How to Create a Data and Safety Monitoring Board (DSMB) 1. Utilize a charter document to capture all the necessary information. Contact the Office of the IRB for DSMB template charters. Version: 7/22/13 Office of IRB 5

6 Appendix: Data and Safety Monitoring Plan Templates Below are templates for protocol language for (DSMPs) for Minimal Risk, Moderate Risk and High Risk studies. After choosing the appropriate template, it should be modified to reflect the unique attributes of the study. The final plan can be added to the protocol document. (Please note that minimal risk studies that do not involve drugs or devices often do not require a DSMP contact your IRB case manager if you have questions.) Example: DSMP for a Minimal Risk Study The principal investigator is responsible for monitoring the data, assuring protocol compliance, and conducting the safety reviews at the specified frequency [e.g., monthly, quarterly, etc]. During the review process the principal investigator will evaluate whether the study should continue unchanged, require modification/amendment, or close to enrollment. The principal investigator, the Institutional Review Board (IRB) or [enter the names of other oversight bodies that have this authority, e.g., NS-LIJ Cancer Center Data and Saf have the authority to stop or suspend the study or require modifications. This protocol presents minimal risks to the subjects and adverse events or other problems are not anticipated. In the unlikely event that such events occur, serious and unanticipated and related adverse events or unanticipated problems involving risks to subjects or others will be reported in writing within 48 hours to the IRB (using the appropriate forms from the website) and any appropriate funding and regulatory agencies. The investigator will apprise fellow investigators and study personnel of all adverse events that occur during the conduct of this research project [describe how the investigator will meet this obligation, e.g., through regular study meetings, via as they are reviewed by the principal investigator.] [Where appropriate, modify the following sentence to apply to the specific research protocol.] The protocol s research monitor(s), e.g., industrial sponsor, Cancer Services Research Review Committee (CSRRC), DSMBs, study sponsors, funding and regulatory agencies, and regulatory and decision-making bodies will be informed of [specify types of adverse events that require reporting to these oversight bodies] adverse events within 5 days [enter other appropriate duration] of the event becoming known to the principal investigator. Example: DSMP for a Moderate Risk Study 1. Personnel responsible for the safety review and its frequency: The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and conducting the safety reviews at the specified frequency which must be conducted at a minimum of every 6 months (including when reapproval of the protocol is sought). During the review process, the principal investigator (monitor) will evaluate whether the study should continue unchanged, require modification/amendment, or close to enrollment. Either the principal investigator, the IRB or [enter the names of other oversight bodies that have this authority, e.g., NS-LIJ Cancer Center Data and Safety Monitoring Committee (DSMC)] have the authority to stop or suspend the study or require modifications. Version: 7/22/13 Office of IRB 6

7 2. The risks associated with the current study are deemed moderate for the following reasons: (choose those that apply) 1. We do not view the risks associated with the as minimal. 2. We do not view the risks associated with the combined use of and as minimal. 3. Given the now established safety and validity of the current in our prior work, we do not view the proposed studies as high risk. 4. Given our experience with the combined co-administration, we do not view the proposed studies as high risk. Although we have assessed the proposed study as one of moderate risk, the potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to predict with certainty the absolute risk in any given individual or in advance of first-hand experience with the proposed study methods. Therefore, we provide a plan for monitoring the data and safety of the proposed study as follows: 3. Attribution of Adverse Events: Adverse events will be monitored for each subject participating in the study and attributed to the study procedures / design by the principal investigator (Insert Investigator Name) according to the following categories: a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s)/agent(s). e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s). 4. Plan for Grading Adverse Events: The following scale will be used in grading the severity of adverse events noted during the study: 1. Mild adverse event 2. Moderate adverse event 3. Severe 5. Plan for Determining Seriousness of Adverse Events: Serious Adverse Events: In addition to grading the adverse event, the PI will determine whether the adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it: 1. is life-threatening OR 2. results in in-patient hospitalization or prolongation of existing hospitalization OR 3. results in persistent or significant disability or incapacity OR 4. results in a congenital anomaly or birth defect OR 5. results in death OR 6. 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, OR 7. adversely affects the risk/benefit ratio of the study Version: 7/22/13 Office of IRB 7

8 An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is important for the PI to consider the grade of the event as well as its seriousness when determining whether reporting to the IRB is necessary. 6. Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse events occurring at a greater frequency than expected, and other unanticipated involving risks to subjects or others to the IRB problems The investigator will report the following types of adverse events to the IRB: a) serious AND unanticipated AND possibly, probably or definitely related events; b) anticipated adverse events occurring with a greater frequency than expected; and c) other unanticipated problems involving risks to subjects or others. These adverse events or unanticipated problems involving risks to subjects or others will be reported to the IRB within 48 hours of it becoming known to the investigator, using the appropriate forms found on the website. 7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol s research monitor(s), e.g., industrial sponsor, NS-LIJ Cancer Center Data and Safety Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and regulatory agencies, and regulatory and decision-making bodies. For the current study, the following individuals, funding, and/or regulatory agencies will be notified (choose those that apply): All Co-Investigators listed on the protocol. Sponsor National Institutes of Health Food and Drug Administration (Physician-Sponsored IND # ) Medical Research Foundation (Grant ) The principal investigator (Insert Investigator Name) will conduct a review of all adverse events upon completion of every study subject. The principal investigator will evaluate the frequency and severity of the adverse events and determine if modifications to the protocol or consent form are required. Example: DSMP for High Risk Study (Please note: in addition to a DSMP, a DSMB may be required) 1. Personnel responsible for the safety review and its frequency: The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and conducting the safety reviews at the specified frequency which must be conducted at a minimum of every 6 months (including when re-approval of the protocol is sought). During the review process, the principal investigator (monitor) will evaluate whether the study should continue unchanged, require Version: 7/22/13 Office of IRB 8

9 modification/amendment, or close to enrollment. Either the principal investigator, the IRB or [enter the names of other oversight bodies that have this authority,] have the authority to stop or suspend the study or require modifications. 2. The risks associated with the current study are deemed high for the following reasons: (choose those that apply) 1. We do not view the risks associated with the as minimal/moderate. 2. We do not view the risks associated with the combined use of and as minimal/moderate. 3. Given the now established safety and validity of the current in our prior work, we do not view the proposed studies as minimal/moderate. 4. Given our experience with the combined co-administration, we do not view the proposed studies as minimal/moderate. Since it is not possible to predict with certainty the absolute risk in any given individual or in advance of firsthand experience with the proposed study methods, we provide a plan for monitoring the data and safety of the proposed study as follows: 3. Attribution of Adverse Events: Adverse events will be monitored for every subject participating in the study and attributed to the study procedures / design by the principal investigator (Insert Investigator Name) according to the following categories: a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). d.) Unlikely: Adverse event is likely not to be related to investigational procedures(s)/agent(s). f.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s). 4. Plan for Grading Adverse Events: The following scale will be used in grading the severity of adverse events noted during the study: 1 Mild adverse event 2 Moderate adverse event 3 Severe adverse event 5. Plan for Determining Seriousness of Adverse Events: Serious Adverse Events: In addition to grading the adverse event, the PI will determine whether the adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it: 1. is life-threatening OR 2. results in in-patient hospitalization or prolongation of existing hospitalization OR 3. results in persistent or significant disability or incapacity OR 4. results in a congenital anomaly or birth defect OR 5. results in death OR 6. 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, OR Version: 7/22/13 Office of IRB 9

10 7. adversely affects the risk/benefit ratio of the study An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is important for the PI to consider the criteria described on the Reportable Event Form before submitting the event to the IRB. 6. Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse events occurring at a greater frequency than expected, and other unanticipated problems involving risks to subjects or others to the IRB. The investigator will report the following types of adverse events to the IRB: a) serious AND unanticipated AND possibly, probably or definitely related events; b) anticipated adverse events occurring with a greater frequency than expected; and c) other unanticipated problems involving risks to subjects or others. These adverse events and unanticipated problems involving risks to subjects or others will be reported to the IRB within 48 hours of it becoming known to the investigator, using the appropriate forms found on the website. 7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol s research monitor(s), e.g., industrial sponsor, the DSMB, study sponsors, funding and regulatory agencies, and regulatory and decision-making bodies. For the current study, the following individuals, funding, and/or regulatory agencies will be notified (choose those that apply): All Co-Investigators listed on the protocol. Sponsor National Institutes of Health Food and Drug Administration (Physician-Sponsored IND # ) Medical Research Foundation (Grant ) The principal investigator (Insert Investigator Name) will conduct a review of all adverse events upon completion of every study subject. The principal investigator will evaluate the frequency and severity of the adverse events and determine if modifications to the protocol or consent form are required. Version: 7/22/13 Office of IRB 10