Data and Safety Monitoring

Katharine Cooper-Arnold, MPHClinical Research Coordinator, Office of Clinical Research

National Heart, Lung, and Blood Institute

Donna JonesProgram Analyst, Office of Clinical Research

National Heart, Lung, and Blood Institute

Georgetown University March 27, 2014

What is OCR? What is a Data and Safety Monitoring Plan (DSMP)? What are the DSMP Elements? What are the NIH and NHLBI DSMP Policies? What is a Data and Safety Monitoring Board (DSMB) Case Studies FAQs DSM links

Agenda

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Who we are: Gail Pearson, MD, Sc.D., Director Katharine Cooper-Arnold, MPH, Clinical Research

Coordinator Donna Jones, Program Analyst

NHLBI Office of Clinical Research (OCR)

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What does OCR do: Serves as a forum for discussion, analysis, and guidance

for the conduct and oversight of NHLBI-funded clinical research

Manages clinical research projects: - DSMB system- Certificates of Confidentiality- ClinicalTrials.gov- Presentations and trainings- Policies and SOPs- Special projects

NHLBI Office of Clinical Research (OCR)

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What is Data and Safety Monitoring (DSM)?

Data and safety monitoring is the process for reviewing data from an ongoing clinical research study to ensure:

Subject safety

Data validity and integrity

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DSMP is the blueprint that describes the procedures for appropriate oversight and monitoring of the study’s conduct

A DSMP is commensurate with the risks involved with the investigation: A DSMP can be as simple as the investigator and site IRB

overseeing the data and safety of the subject

OR As complex as having a Data and Safety Monitoring Board

What is a Data and Safety Monitoring Plan (DSMP)?

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DSMPs include procedures for: Identifying study oversight responsibilities Managing subjects’ risks Monitoring study procedures Collecting and reporting serious adverse events (SAEs), adverse

events (AEs), unanticipated problems (UPs), and reporting timeframes

Protecting confidentiality Ensuring compliance across sites for multi-center trials Ensuring appropriate termination of studies

What Procedures do DSMPs Include?

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DSMPs include: Safety and reporting plans Monitoring plans Data management plans

- Study data reviews for accuracy and completeness Statistical analysis plans

- Planned interim analysis

DSMPs Can Include Multiple Study Plans

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Study phase Trial design Regulatory compliance Disease under study Study intervention Study population (e.g., vulnerable populations) Study outcomes/variables Conflicts of interest AND, the degree of risk to which participants in the trial are

exposed

What Should I Consider in Designing a DSMP?

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An appropriate monitor (person or group) Monitoring procedures and frequency of monitoring Content of DSM report submitted by the PI Collection/reporting of adverse events to IRB, FDA, and NHLBI Reporting mechanisms for amendments to the protocol or consent Potential risks and benefits to subjects IND or IDE information Conflicts of interest Data analysis plans Trial stopping rules Plans for interim analysis DSMB/OSMB plan

The NHLBI Checklist has Helpful DSMP Elements

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Q: If an institution does many small trials in different phases and disease areas, how might they structure their DSMPs?

A: Choose a plan formulated in modules Each module describes in adequate detail how monitoring will be

accomplished for a major class of trials that the institution supports: E.g., early-phase studies in treatment, behavioral studies, bone-marrow

transplantation, chemoprevention studies in healthy populations, etc. Investigators can then apply these plans to particular protocols with little

or no change in the description

Case Study

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June 1998 -NIH issued their data and safety monitoring policy: IRB review of all extramural research involving human subjects/

identifiable human specimens before NIH funds are released IRB-approved DSMP for all interventional trials Appointment of a Data and Safety Monitoring Board (DSMB) for

all clinical trials that involve:- Investigation of a research question having direct

implications for clinical care and/or public health (including all phase III trials), and/or

- High-risk intervention, and/or - Highly vulnerable patient population

What is the DSM Policy for NIH-funded Research?

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October 2000 - NIH-funded PIs must also submit a DSMP for phase I/II clinical trials to the funding institute (IC) before the trial begins

At a minimum, all DMSPs must include a description of the reporting mechanisms of AEs to the IRB, the FDA, and the NIH

ICs have the flexibility to determine AE reporting requirements

NIH Data and Safety Monitoring Policy - Early Phase Trials

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Why Do Phase I/II Trials Need a DSMP?

In phase I/II trials, a number of factors influence risk: Phase I trial of a new drug may involve increasing risk, as the

drug is escalated in dosage Phase II trial risk may be increased as more participants are

involved with toxicity/outcomes confounded by the disease process

- In situations involving potentially high risks or special populations, investigators must consider additional monitoring safeguards to the DSMP

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In addition to the NIH requirements, the NHLBI also requires: IRB-approved DSMPs prior to study funding for all human

subjects research that involves greater than minimal risk to participants (as determined by the IRB)

NHLBI Data and Safety Monitoring Policy

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Outlines the requirements for data and safety monitoring of clinical studies for all human subjects research funded in whole or in part by the NHLBI

Maintains compliance with the NIH mandate by making the NHLBI program/project officer (PO) responsible for oversight of data and safety monitoring

Makes clear that the role of the NHLBI is to ensure that appropriate approvals have been obtained

And, requires that release of funds for NHLBI human subjects research activities is contingent upon compliance with this policy

But, it does NOT… Usurp the role of IRBs or other regulatory and monitoring bodies

What Does the NHLBI DSM Policy Do?

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Q: A two-arm, randomized NIH-funded interventional study involves only moderate risk to subjects. Does it need a DSMP?

A: Yes, for NIH-funded studies, documentation of an IRB-approved data and safety monitoring plan is necessary for all interventional trials

Case Study

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DSMPs, when required, must: Identify the person or organization that will monitor the study.

Monitoring may be performed by:- The PI- An independent monitoring group- DSMB or OSMB

– For studies with low risk, monitoring by the PI and the IRB may suffice

– For higher risk studies, a DSMB may be required. Receive IRB approval for all clinical research proposals Describe procedures for ensuring compliance with the DSMP

and for reporting across study sites for multi-site studies

NHLBI Data and Safety Monitoring Implementation

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A NHLBI program official (PO) reviews the IRB-approved DSMP prior to funding

If an IRB-approved DSMP is not received for a study that, in the opinion of the PO, requires one: NHLBI may request certification that the IRB has concluded that

the proposed research is neither a clinical trial nor a study that involves greater than minimal risk

How Does NHLBI Review a DSMP?

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NHLBI monitors a DSMP through: Accrual process Participation in DSMB meetings if NHLBI DSMB; through review

of DSMB minutes if local DSMB Review of SAEs Review of standard grant reporting (e.g., investigator reports

related to DSMP issues)

How is a DSMP Monitored by NHLBI?

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Q: A multi-center IND pilot trial will compare an investigational immunosuppression product to standard of care. Does it need an NHLBI DSMB?

A: Yes, because it is a multi-center, high-risk study An IND is in place Quality-control procedures are generally stipulated by the IND sponsor

and the FDA regulations and may be simply referenced or summarized in the DSMP

Refer to FDA regulations 21 CFR 312

Case Study

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A group of individuals that play different roles in clinical trial monitoring Usually appointed by a sponsor/funder

Pharma may call them Data Monitoring Committees (DMCs)

What is a Data and Safety Monitoring Board (DSMB)?

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Protects the safety of participants Evaluates trial equipoise

Ensures the integrity and credibility of the trial Ensures that research objectives & questions can be

met and answered Identifies beneficial treatments early

Stops trial early if treatment is ineffective Ensures that reliable results are available to the medical

community in a timely fashion

What is the Purpose of a DSMB

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It is important to have multiple disciplines represented including: Trial-specific medical/clinical experts Statisticians Ad hoc experts (bioethicists, epidemiologists,

scientists) Patient representatives, when appropriate

Who Can be a DSMB Member?

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NIH requires the appointment of a DSMB for all clinical trials that involve: Investigation of a research question having direct implications for

clinical care and/or public health (including all phase III trials)

For earlier trials (phase I/II), a DSMB may be appropriate if studies: Have multiple clinical sites Are blinded (masked) Employ high-risk interventions or vulnerable populations

NIH DSMBs

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When is a DSMB/OSMB appointed by NHLBI? For multi-center trials, research networks For high-risk and/or vulnerable populations, and for other clinical trials

performed under a contract or a cooperative agreement For epidemiologic studies/registries involving multiple sites and/or

conducted under a contract or cooperative agreement, an OSMB may be appointed or ask the institution to appoint one 

For all other clinical trials, a DSMB can be appointed by the awardee institution

NHLBI DSMBs

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Q: An NHLBI-funded study is phase Ib with 2 sites and is using a new cell-based therapy. Does it require an NHLBI or an institutional DSMB?

A: Monitoring is commensurate with risks and with the size and complexity of the trials. All intervention studies (e.g., clinical trials), regardless of the phase, must have ongoing data monitoring. The NHLBI requires DSMBs for phase III clinical trials. But even with a phase 1B study, NHLBI would consider that a new cell-

based therapy is of sufficient risk to have a DSMB, and if it is multi-site, it would likely rise to the level of needing an NHLBI DSMB. 

These decisions are discussed with program staff on a case-by-case basis.

Case Study

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Q: A new pediatric multi-center trial that is part of a research network will use an investigational device, and the study will be performed under an NIH-funded cooperative agreement. What type of a DSMB should they consider?

A: An NHLBI-organized DSMB since the study has: Multiple centers Vulnerable population IDE (increases risk)

Case Study

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What Elements Belong in the DSMB Charter?

DSMB responsibilities Conflicts of interest Other players How are meetings structured? Who is blinded? Logistics Indemnification of DSMB members, if applicable (not for NIH DSMBs) Regulatory Issues Stopping a trial Channels of communication Statistical monitoring guidelines

Stopping rules

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Reviews data safety and quality Reviews enrollment data to ensure proper trial conduct Reviews the informed consent form when it reviews the protocol Reviews current literature to assess any new risks that might affect

the protocol/informed consent May review formal interim analyses of the primary end point Monitors overall study conduct Makes recommendations to the sponsor, funder

What specifically does the DSMB Do?

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Q: PI reported to program staff who told the DSMB that data outside the trial might impact the conduct of the trial. What if anything should the DSMB do?

A: DSMB asked whether these data might suggest that the study impacted the risk to the participants, and whether the study should be continued. A special DSMB meeting was held with the external data, and the

DSMB recommended study closure. The Institute accepted the recommendation and closed the study to further entry, including discontinuing the intervention for any participants enrolled who were still on treatment.

Case Study

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Q: A PI has determined that her research protocol has only minimal risk. Is this study exempt from a DSMP under NHLBI policy?

A: Not necessarily since the PI cannot make that determination. The IRB, not the PI, determines the level of risk.  If the IRB

determines that the study is minimal risk, no DSMP is required.  

Case Study

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Q: How does the NHLBI policy differ from the NIH policy?

A: The NHLBI policy is aligned with the NIH policy and extends the requirement of DSM plans to include clinical research with greater than minimal risk in addition to clinical trials. The NHLBI policy explicitly requires IRB approval of the DSM

plan. 

DSM FAQs

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Q: Does the NHLBI data and safety monitoring policy apply to all award mechanisms used by NHLBI?

A: Yes, this policy applies to all NHLBI-sponsored research projects regardless of whether they are contracts, grants, or cooperative agreements.

DSM FAQs

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DSM FAQs

Q: My data and safety monitoring plan is part of my grant application. Is this sufficient, or am I required to send something else?

A: NHLBI Policy requires an IRB-approved DSM plan. The DSM plan in your grant application is sufficient if: It contains the essential elements listed in the NHLBI policy and Your institutional business official documents that your IRB has

reviewed and approved the relevant section of your grant application. 

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Q: What happens if I don't provide a DSM plan in my grant application?

A: If your application is selected for funding and is either a clinical trial or clinical research entailing more than minimal risk, NHLBI will place a term and condition on the Notice of Award (NoA) restricting all human subjects research activities until the grantee can demonstrate that the IRB has reviewed and approved the DSM plan. A similar process is followed for contracts.

DSM FAQs

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Q: What if the human subjects aspect of my research begins after the first year of funding?

A: The NIH data and safety monitoring policy only applies to human subjects research. For example, if the human subjects research portion of your study begins in year 3, then this policy must be followed prior to the commencement of human subjects research activities starting in year 3. Other research activities that do not involve human subjects may

proceed.

DSM FAQs

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Q: What should I do if there are changes in human subjects research risk or changes to the DSM Plan?

A: Modifications to the human subjects research or DSM plan should be submitted to the NHLBI GMO or CO prior to implementation of the change in study practice. The program officer should be copied on all communication. 

DSM FAQs

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Q: How do I determine if this clinical research grant requires an institutional or NHLBI DSMB?

A: The NHLBI adds studies to existing NHLBI DSMBs or appoints NHLBI DSMBs for: Phase III clinical trials Institute-initiated clinical trials in which the scientific concept originated with

NHLBI, regardless of funding mechanism, including networks and contracts Trials of interventions for cell-based therapies/gene therapies Investigator-initiated clinical trials supported by cooperative agreements, at the

discretion of the NHLBI Selected investigator-initiated trials with direct costs >$500,000/year.

A: DSMBs may be appointed by participating institutions in coordination with NHLBI program for: All clinical trials not cited under the section above. Early-phase, single-center investigator-initiated studies. The need for a DSMB

will be determined by the PI, although NHLBI program will independently evaluate the need for a DSMB by the time the monitoring plan is reviewed.

DSM FAQs

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http://grants.nih.gov/grants/guide/notice-files/not98-084.html http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm

Helpful NIH DSM Links

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To the following for their review and guidance Gail Pearson David Gordon Erin Iturriaga Ruth Kirby Victoria Pemberton Wendy Taddei-Peters

Thank you

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Questions

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