The Importance of Real-time Data and Safety Monitoring
Researchers at Baylor College of Medicine Houston announced this week that they were stopping a clinical trial investigating the efficacy of convalescent plasma therapy in the treatment of patients with COVID-19. The reason, according to the principal investigator, was that statisticians had deemed the NIH-funded study to be futile. In other words, even with more patients enrolled in the study, the experts monitoring the data did not believe there was a realistic chance that convalescent plasma therapy would demonstrate efficacy.
Behind the headline is another important consideration: the importance for Institutional Review Boards (IRBs) to ensure that studies they approve have strong data and safety monitoring plans (DSMP). Data and safety monitoring functions are distinct from the requirement for study review and approval by an Institutional Review Board (IRB).
“Since IRB review occurs only at certain intervals, real-time data monitoring is typically done by a formal Data Safety Monitoring Board (DSMB) or another similar independent committee, as designated by the DSMP,” according to Linda Reuter, BRANY’s IRB Director. “As such, it is crucial for IRBs to consider the IRB approval criteria that risks to subjects are minimized and the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects by confirming that there is a plan to analyze the data at the appropriate intervals.”
“The IRB must determine that the provisions for data and safety monitoring are appropriate in order to approve a protocol,” adds Raffaella Hart, BRANY’s Sr Vice President for IRB and IBC Services. “Clinical trials should have a provision for data and safety monitoring that corresponds to the risks of the study.” The NIH has guidance on determining which studies require a Data and Safety Monitoring Board (DSMB). Multi-site clinical trials involving interventions that entail potential risk to the participants require DSMBs.
Review by an independent monitoring committee is especially important for multicenter clinical trials, as data from one site may not be enough to notice a safety signal at an early stage, but when data from multiple sites are aggregated and analyzed by the safety committee certain safety signals may become evident.
The method and degree of monitoring varies from one clinical trial to another and is based on the degree of risk involved, as well as the size and complexity of the trial. While not all clinical trials require a data and safety monitoring board, the NIH does set minimum standards for monitoring, including ensuring that monitoring is timely and effective and that those responsible for monitoring have the appropriate expertise to accomplish its mission. Monitoring plans typically include the following:
- Safety reporting requirements and procedures
- Rules for when to conduct interim analyses to assess safety and/or efficacy
- How the study will comply with any applicable regulatory requirements
- How the study will monitor site performance, including patient recruitment
- How to protect data integrity and participant confidentiality
- Statistical analysis procedures
Data and Safety Monitoring Board determines the safe and effective conduct of the trial, and establishes rules for deciding when it may be time to conclude the trial. The committee makes this important decision based on evaluating if significant benefits or risks have developed or the trial is unlikely to be concluded successfully. This was the case in the above-mentioned plasma therapy trial. DSMBs should include clinical trial experts, biostatisticians, bioethicists, and clinicians knowledgeable about the disease and treatment under study. Ideally, members should not have a vested interest in the outcome of the study, in order to avoid conflicts of interest.
“Early and ongoing data analysis is critical to the safety and protection of study participants,” says Ms. Reuter.
Critical Considerations for Remote Clinical Trials
Even as research centers and academic institutions re-open after shutdowns due to COVID-19, many researchers are looking at ways to use remote technologies in their clinical trials. In South Carolina, for example, nicotine addiction researchers are examining how to enroll smokers in their studies. They are evaluating e-consents, online surveys and questionnaires, as well as smartphone-enabled devices.
Historically, patient enrollment in clinical research has been a significant challenge. According to research by the National Institutes of Health, 80 percent of clinical trials fail to reach their enrollment goals within the prescribed timelines. Some sites fail to recruit a single participant.
Social media is a promising way to recruit potential research subjects. With its current ubiquity, social media enables researchers to reach broad populations and target subjects based on personal information. They can also reach physicians and other clinical practitioners to inform them of new trials.
However, there are important risks to manage, including privacy and transparency. Researchers who join online patient communities — for example, those focused on a particular diagnosis — should be clear of their role.
Learn more about Social Media and Research Recruitment in this webinar: Citi Program course informed consent and clinical investigations a focus on the process
Obtaining informed consent via electronic methods involves more than just video conferencing technology. E-consents require an adjustment in processes, which can be an adjustment for research coordinators or others obtaining consent. Proper training on process is critical to ensure informed consent is obtained appropriately and the rights and welfare of human subjects are continually protected.
Implementing e-consent also requires assurance that the technology platforms are in compliance with FDA requirements for electronic signatures. Institutions must consider issues such as privacy and data security.
Learn more about remote informed consent: https://www.brany.com/telehealth-clinical-research-and-informed-consent/
Virtual Patient Visits and Wearables
Investigators who are writing protocols must consider opportunities for virtual patient visits that will minimize exposure to clinical environments such as hospitals and clinics. The use of telemedicine technologies has exploded in 2020, as clinicians worked to maintain continuity of care during lockdown.
One critical element to consider for virtual patient visits is to include them in the budget. Recent news reports about insurance coverage of telemedicine visits demonstrate some shifts in reimbursement.
COVID-19 presented many challenges to clinical researchers. But it also offered many opportunities to revolutionize how investigators think about writing protocols, and how patients can enroll and participate in them. The landscape continues to shift rapidly, and requires careful monitoring to ensure both compliance and patient protection.
New CITI Program Courses and Webinar Help Researchers and Institutions Meet Regulatory Requirements
(Miami, FL) — The Collaborative Institutional Training Initiative (CITI Program), a division of BRANY, has announced new online courses and webinars designed to help research professionals understand and comply with regulatory requirements for clinical trials.
The three courses and webinars address critical regulatory requirements:
- Transitioning research to the Revised Common Rule
- Protocol registration and disclosure on ClinicalTrials.gov
- The role of principal investigators in meeting regulatory requirements
Transitioning Research to the Revised Common Rule: The What, How, and Why, a webinar that outlines considerations and challenges for transitioning pre-existing research to the revised Common Rule, as well as required documentation and tips for IRB review, is offered to both institutions and individual learners.
Designed for research professionals, including investigators, institutional review boards and research staff, the webinar reviews pre-2018 and 2018 versions of the Common Rule, including factors an organization may want to consider when deciding whether to transition a pre-existing study (or studies) to comply with the revised Common Rule, and strategies for the management and communication of transition decisions.
The webinar is presented by Karen Christianson, RN, BSN, a principal with HRP Consulting Group.
Recently published research demonstrates that many research institutions are not prepared to meet current requirements for registering and reporting clinical trials. A new course addresses this gap.
Protocol Registration and Results Summary Disclosure in ClinicalTrials.gov, an innovative video-enhanced course, guides learners through critical parts of the regulations and provides a step-by-step guide to data entry. This course can help organizations/investigators clearly understand protocol registration requirements to avoid the risk of significant civil monetary penalties or loss of NIH grant funding due to non-compliance with protocol registration and results reporting.
Biomedical PI focuses on key topics essential to the biomedical investigator’s role and responsibilities in conducting a clinical investigation of a product regulated by the U.S. Food and Drug Administration (FDA). This role-based course covers supervision, delegation, management, reports, and communication for investigators.
These courses, along with dozens of others available at CITIprogram.org, train investigators and research professionals to understand and meet research ethics standards and compliance requirements.
About CITI Program
The Collaborative Institutional Training Initiative (CITI Program), a division of BRANY, is dedicated to promoting the public’s trust in the research enterprise by providing high quality, peer-reviewed, web-based educational courses in research, ethics, regulatory oversight, responsible conduct of research, research administration, and other topics pertinent to the interests of member organizations and individual learners.
Gene Therapy Research — Is Your Institution Ready?
Recent news about approved immunotherapy and gene therapies has generated excitement around the possibilities of treating difficult diseases. Organizations have increased funding in this area, including a recently announced $1.3 million grant in funding by the Alliance for Cancer Gene Therapy for research in gliobastoma, sarcoma and ovarian cancer.
The increased attention and funding means that more research institutions may enter this exciting field of research. However, institutions may not be fully aware of the specific NIH guidelines and requirements for gene transfer research in addition to IRB review. An institution that receives NIH funding or conducts NIH funded recombinant DNA research is required to follow the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (“NIH Guidelines”). Even if the funding source is a private entity, it is still advised that institutions comply with the NIH Guidelines to ensure the safety of research teams and the communities they serve.
The NIH Guidelines define human gene transfer as the deliberate transfer into human research participants of either:
- Recombinant nucleic acid molecules
- DNA or RNA derived from recombinant nucleic acid molecules
- Synthetic nucleic acid molecules, or
- DNA or RNA derived from synthetic nucleic acid molecules that meet certain criteria
An institution that engages in gene transfer must establish an institutional biosafety committee (IBC). This committee can be administered either internally (by the institution), or by an experienced external group. The IBC must have at least five members, two of whom must not be affiliated with the institution. The role of the IBC is distinct from the role of an Institutional Review Board (IRB). The IRB’s focus is on protecting the rights and welfare of research participants, whereas the IBC assesses the containment levels, facilities, procedures, practices, and training and expertise of personnel involved in recombinant or synthetic nucleic acid molecule research.
Research involving recombinant or synthetic nucleic acid molecules requires IBC review because additional safety measures are needed. The risk assessment for these agents must be done by qualified experts experienced in biosafety guidelines, including physical and biological containment requirements. Those conducting this research need to understand and identify the biosafety level of the particular investigational agent — level one being the lowest level and level four being the highest. Each level has specific parameters that must be met with relation to precautions needed, such as containment levels, staff training requirements, and the experience required of those handling the agent.
Risk is assessed by evaluating the following:
- Staff training — are they trained in handling the agents according to guidelines and standard operating procedures?
- Protocol — does the protocol outline how the agents are handled, including waste precautions and decontamination procedures?
- Recordkeeping — how are records documented and kept?
- Procedures — how and where is the agent or drug constituted?
- Community safety — what mitigation steps are in place to protect the community?
While the prospect and promise of human gene transfer research is exciting, institutions and researchers must understand the requirements when working with these investigational agents.
When research involving recombinant DNA is NIH funded or conducted at a site that receives NIH funding, failure to comply with the NIH Guidelines could risk that funding or result in additional requirements by NIH for the conduct of such research. Leveraging an external team of experts fluent in biosafety, the NIH Guidelines, and IBC administration can provide an immediate framework for an institution to build upon that will ensure the safety of local research teams and the surrounding communities in an ethical and efficient way.