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.
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.
NIH Announces Consortium to Streamline Gene Therapy Research
The National Institutes of Health (NIH) announced this week that they were joining forces with the Food and Drug Administration (FDA), ten pharmaceutical companies and five non-profit organizations to accelerate the development of gene therapies for rare diseases. The new public-private partnership, called the Bespoke Gene Therapy Consortium, aims to overcome obstacles and streamline the process of developing therapies that could treat diseases that collectively impact millions of people.
The consortium will fund basic and clinical research from a five-year budget of $76 million. This represents an opportunity for investigators. For institutions interested in participating in the expected clinical trials, it may be time to revisit their policies for biosafety and gene transfer. Institutional Biosafety Committees (IBC) are required at institutions that conduct NIH-funded recombinant DNA, or gene therapy, research.
An IBC is concerned for the protection of not only research subjects, but also staff and communities in which the research takes place. The committee has oversight for establishing, monitoring, and enforcing policies and procedures for handling biohazardous materials, such as recombinant DNA.
An IBC works in parallel with an Institutional Review Board (IRB), with special attention to risk assessment for areas including:
- Study agent
- Containment levels and procedures required to safely handle the study agent
- Preparedness of the facility and its personnel
- Potential impact to the environment
Activities of the IBC include:
- Review agent characteristics (e.g. virulence, pathogenicity, environmental stability)
- Determining the appropriate biosafety level for physical and biological containment, as required by the NIH Guidelines
- Inspection of facilities, procedures, and practices
- Evaluating the training and experience of the personnel involved in the research
- Confirming appropriate policies and procedures are in place for handling spills or accidents to minimize exposure to or contamination from any potentially hazardous material
- Reporting significant events or violations to regulatory authorities including NIH and institutional officials
- File an annual report with the NIH
NIH requires that an IBC have at least five members who collectively have broad experience and expertise that allows them to conduct such assessments. This may include members with technical expertise in potentially hazardous biological materials, human research protocols, regulatory requirements, and in the health and protection of the community and environment. Additionally, at least two members must be unaffiliated with the organization conducting the research, and these members should represent the interest of the surrounding community with respect to health and protection of the environment.
The establishment and funding of the Bespoke Gene Therapy Consortium will increase the opportunity for investigators to participate in basic and clinical research to address significant unmet medical needs of patients. The safe conduct of experiments involving recombinant or synthetic nucleic acid molecules depends on the individual conducting such activities, as well as having appropriate safety mechanisms at the institutional level.
BRANY offers IBC services that can help expedite the review of research that involves recombinant DNA (“rDNA”) or synthetic nucleic acid molecules, or DNA or RNA derived from recombinant or synthetic nucleic acid molecules, providing rigorous biosafety oversight so that institutions can focus their efforts on scientific research and advancement. Contact us for more information.
FDA Updates Guidance for Clinical Trials During COVID-19 Pandemic
In March 2020, as governments around the world were issuing large-scale lockdowns, health facilities shifted their efforts to addressing critical needs of patients while trying to maintain the safety of staff. Clinical trials ended or were paused, and researchers allocated their attention and resources to understanding and managing the novel coronavirus.
To assist researchers, IRBs, and sponsors, the FDA issued guidance last year on the conduct of clinical trials during the COVID-19 pandemic. The guidance aimed to help institutions protect clinical trial participants, maintain compliance with Good Clinical Practice, and ensure data integrity of the research. Among the many challenges brought on by COVID-19, some of the most vexing logistical challenges came from quarantines, site closures, travel limitations, and interruptions of the supply chain for investigational or other products. In addition, institutional leaders have had to address considerations if site personnel or trial participants became infected with COVID-19.
The FDA recently updated this guidance, in August 2021. This is a high-level review of some of the issues addressed in the guidance.
Deviations from a protocol may be necessitated by changes to public health recommendations both at the national and local levels. Also, deviations can occur in the case of exposure, a positive test, or diagnosis of a trial participant.
Deviations can include a change in how patients are monitored — from in-person to remote visits, for example. COVID-19 has increased the acceptance of these alternative methods of monitoring, reducing unnecessary travel and risk of exposure for participants. For the safety of participants, sponsors may consider options such as phone calls, virtual visits, or even remote monitoring devices.
Some changes to the protocol or investigational plan are intended to minimize or eliminate immediate hazards or to protect the life and well-being of research participants. In these urgent cases, deviations may be implemented without IRB approval or before filing an amendment to the investigational new drug (IND) or investigational device exemption (IDE) However, they are required to be reported afterwards.
Investigators should work closely with IRBs to ensure policies and regulatory requirements for reporting deviations are followed and, when needed, develop plans or procedures to prioritize reporting of deviations that may impact the safety of trial participants.
Additional Screening Procedures
Institutions may require COVID-19 screening of clinical trial participants. In these cases, the screening does not need to be reported as an amendment to the protocol, even if done during clinical study visits.
On the other hand, if the sponsor is incorporating the data collected as part of a new research objective, it should be reported as a change to the protocol. This additional protocol-driven screening should also be considered in the clinical trial budgeting process.
The Importance of Documentation
Sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes. They should indicate which trial participants were impacted, and how those trial participants were impacted.
Some changes, such as an adjustment in a study visit schedule, may lead to missing information. In those cases, it is important to capture in the case report what specific data is missing and the reason for its absence.
Other items that sponsors should document:
- Contingency measures implemented to manage disruptions due to COVID-19
- A list of all participants who were impacted by COVID-19-related study disruptions, and how they were impacted
- Analysis of how contingency measures may have impacted safety and efficacy results
Protecting Data Integrity
Sponsors that anticipate that changes to the protocol will impact data management procedures or statistical analysis plans should coordinate with their respective FDA review division. This includes situations in which the efficacy endpoints may be impacted. For example, assessments may be conducted virtually instead of in-person. Any modifications to the data management or statistical analysis plan but also receive IRB review and approval.
Questions and Answers
The guidance also contains an appendix with 28 questions along with detailed answers for each question. Some of the topics covered include:
- re-monitoring after pandemic related restrictions are lifted
- exclusion criteria for “investigational medical products”
- collecting electronic signatures and Part 11 compliance
- reviewing IND safety reports
Twenty months after the first COVID-19 case was confirmed in the United States, researchers are still trying to understand the long-term impact on non-COVID clinical trials. Researchers and clinical trial professionals have had to demonstrate resilience, flexibility, and adaptation in the face of uncertainty and a changing epidemiological landscape.
The primary guiding principle throughout the guidance is to ensure the safety of clinical trial participants.
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:
- Electronic Records; Electronic Signatures (21 CFR Part 11)
- Regulatory Hearing Before the Food and Drug Administration (21 CFR Part 16)
- Protection of Human Subjects (Informed Consent) (21 CFR Part 50)
- Financial Disclosure by Clinical Investigators (21 CFR Part 54)
- Institutional Review Boards (21 CFR Part 56)
- Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58)
- Investigational New Drug Application (21 CFR Part 312)
- Applications for FDA Approval to Market a New Drug (21 CFR Part 314)
- Bioavailability and Bioequivalence Requirements (21 CFR Part 320)
- New Animal Drugs for Investigational Use (21 CFR Part 511)
- New Animal Drug Applications (21 CFR Part 514)
- Applications for FDA Approval of a Biologic License (21 CFR Part 601)
- Investigational Device Exemptions (21 CFR Part 812)
- Premarket Approval of Medical Devices (21 CFR Part 814)
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.
FDA Guidance for Industry: Investigator Responsibilities
FDA Guidance for Sponsor-Investigators
ACRP Guide to FDA Form 1572
BRANY protocol launch showcases paradigm shift in behavioral and social sciences research
Please read the attached Centerwatch Article to learn how social, educational and behavioral research is distinct from biomedical research when it comes to writing study protocols. cww2131_BRANY