The Future of Work and the Impact on Research Institutions

International organizations such as the World Economic Forum have been researching and analyzing the “future of work” and its implications for economies. Likewise, consulting firms have been predicting the important training needed to prepare workforces for new labor markets. Surveys of company leaders indicate an increasing need for employee upskilling and retraining.

The COVID pandemic and dizzying changes to our work environments accelerated the already-occurring changes in how we work. For research professionals, the changes have impacted how we start-up and manage clinical trials. The breakneck speed with which pharmaceutical companies developed, tested, and deployed COVID vaccines may have been a preview. The clinical trial community should understand the lessons learned from these expedited processes and consider how to prepare for “the next time.”

It remains to be seen which changes will remain for the long term. But some experts say that some permanent changes are inevitable, whether it’s remote patient visits, online collaboration, or remote digital monitoring.

Studies about the future of work tend to focus on the use of artificial intelligence and increased dependency on automation. There are human factors to consider, as well. Managers must define how to run hybrid teams and encourage resilience among workers. The World Economic Forum identifies major changes in three categories:

  • Technology in the form of machine learning, artificial intelligence, and automation
  • Ongoing learning and skill acquisition
  • Talent mobility

This was supported by a report by McKinsey & Company, published in October 2020, that said workers in the life sciences had to double their efforts to focus on patients, leverage technology, and cultivate workplace agility.

Flexible work force

The ability to accommodate the ebb and flow of clinical research activities, or rapid redeployment based on shifting priorities, means that leaders need flexible staffing.

Hybrid work situations will require the need for cross-training among staff and the increased use of external resources to supplement internal staff. Highly responsive teams, augmented by expert hands-on external staff, can ensure sustainability of existing research projects even when new or urgent needs emerge.

Improving patient communication

The requirement to obtain informed consent of individuals before involving them in research is one of the central protections provided for under the HHS regulations at 45 CFR part 46 and  21 CFR 50.

The Revised Common Rule introduced new informed consent standards that focus on providing prospective research participants with information that a reasonable person would want to have in order   to make an informed decision about participation in a research study.  Additionally, the presentation of information to the participant must be organized and include sufficient detail to facilitate the participants understanding of why they may or may not want to join the research study.

These requirements, along with the shift to e-consent and other technologies, have changed not only the language of consent forms but also the process and workflow in obtaining consent.

This is just one example of many patient-centered shifts in the paradigm of clinical research.

Continuous learning

Beyond the required certifications in Good Clinical Practice or foundations for clinical research coordinators, research institutions must offer ongoing upskilling opportunities for staff to keep them up-to-date on the shifting technology and regulatory landscapes of clinical research.

Even prior to the pandemic, online learning was dominating the professional development field. Hiring managers who wanted to cultivate a more diverse and agile workforce were using online solutions such as CITI Program to ensure their skills were up to date.

Leveraging technology for better collaboration and improved workflow

Writing a protocol for a clinical trial has become a complex team sport requiring multidisciplinary input from various sources. Researchers are collaborating with colleagues at their own or other institutions, across clinical disciplines.

The protocol-writing process — from version management to IRB review — can be cumbersome. The use of paper-based systems, or even email, can result in confusion or delays. The result can mean incomplete IRB submissions and frustration for investigators.

Cloud-based guided applications, such as Protocol Builder, can expedite the process by fostering communication and teamwork. These systems build teaching into the writing process, which is essential for residents or new investigators. A complete and compliant protocol submission can result in a smoother IRB review process.

While no one has a crystal ball into the future, many organizations and foresight consultants are in general agreement that the workplace is undergoing a paradigm shift. Research institutions are not immune to these major changes, particularly if they focus on the key areas of change — mobility and flexibility, increased use of technology, and ongoing learning and upskilling.

When an Investigator is also a Sponsor

When investigators embark on designing, writing, and initiating the clinical trial, their responsibilities are just beginning. The FDA calls these investigators “sponsor-investigators (SIs)”. A sponsor-investigator is an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. In other words, in an investigator-initiated trial, the researcher is both the investigator and the sponsor, and therefore must handle the responsibilities for both roles.

The FDA provides guidance for individual investigators planning to conduct clinical investigations of FDA regulated drug(s) or device(s) for an indication that does not appear in the approved labeling for the product. Depending on the origin of the funding for the trial (e.g. federal funding) regulations by the U.S. Department of Health and Human Services Office for Human Research Protections (OHRP), 45 CFR 46 known as The Common Rule, may also be applicable.

In most cases, institutional policies and guidance fall into two major categories: protecting human subjects and ensuring the integrity of the data from clinical investigations. This is true for all research trials.

All investigators in interventional drug studies must complete and submit FDA Form 1572 (21 CFR 312.50), which specifically outlines certain responsibilities and obligations including agreeing to personally conduct and supervise the investigation.

Investigational New Drug (IND) or IDE Applications

Some protocols may require the investigator to submit an investigational new drug (IND) or an investigational device exemption application. However, a sponsor-investigator may not be required to submit an IND for a study of a lawfully marketed drug if the criteria outlined in the FDA regulations at 21 CFR 312.2(b) for an IND exemption are met. Investigators should confirm if the protocol is exempt from this requirement by reviewing the regulations. If sponsor-investigators are uncertain if the exemption criteria are met, they should seek advice from FDA.

For trials involving medical devices, the Investigational Device Exemptions (IDE) regulation (21 CFR 812) must be considered. Under this regulation medical devices are generally categorized as significant risk or nonsignificant risk devices. Significant risk devices studies must have an IDE application approved by FDA before any research may begin.

Conduct Good Clinical Practice (GCP)

GCP is an international ethical and scientific quality standard for clinical trials with a primary objective of protecting human rights. Compliance with this standard helps to provide assurance that the rights, safety, and well-being of trial subjects are protected. FDA has adopted GCP as guidance for carrying out clinical trials. FDA regulations relating to good clinical practice and clinical trials include:

Monitoring and Reporting

Good Clinical Practice (GCP) guidelines also describe the requirements for quality management in clinical trials to further ensure the protection of participants and the reliability of trial results. Investigator-sponsors have specific responsibilities for monitoring trials to confirm the trial is conducted and the data generated, recorded, and reported are in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

The methods used to assure quality should be proportionate to the risks in the trial and the importance of the information collected. Methods for monitoring clinical trials range from on-site data verification to centralized data monitoring using statistical analytics to identify areas of risk.

Investigators who do not comply with these regulations and standard operating procedures run significant risk of liability and federal investigation. The FDA has outlined a specific process for investigating non-compliant investigators that includes disqualifying investigators from further research.

The regulatory landscape is constantly shifting and can pose some challenges, particularly for new investigators. Working closely with regulatory experts through the steps, as well as taking courses on GCP, can minimize the risks, protect patients, and ensure research integrity.

Further resources

FDA Guidance for Industry: Investigator Responsibilities
https://www.fda.gov/media/77765/download

FDA Guidance for Sponsor-Investigators
https://www.fda.gov/media/92604/download

ACRP Guide to FDA Form 1572
https://acrpnet.org/2019/04/25/revisiting-the-form-fda-1572/

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.

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.