Could Diversity in Clinical Trials Become Mandatory?
Initiatives by the FDA, NIH and other regulatory agencies that have urged investigators and sponsors to diversify study populations have been just that: suggestions and recommendations. But a new report by the National Academies of Sciences, Engineering and Medicine is suggesting that regulatory agencies add some bite to their guidance. The organization is recommending enforcement of diversity targets, with federal research funding as both a carrot and a stick.
While the Academies are private, volunteer, non-profit organizations, their consensus reports can have an influence in policy decision-making. The report is authored by a committee of physicians, academics, and patient advocates from a variety of prestigious medical schools, universities, and institutions.
The basis of the report is evidence that “those that often face the greatest health challenges, are less able to benefit from these discoveries because they are not adequately represented in clinical research studies.” The authors recognize the progress in increasing the participation of white women in clinical trials. But it highlights the continued lack of progress among ethnic and LGBTQ communities, as well as elderly populations and those with disabilities.
As the United States continues to become more diverse, the generalizability of clinical research findings is increasingly compromised. This can influence the applicability of health screening guidelines as well as the understanding of therapeutic responses among different populations.
The report also considers health economics in its recommendations. With better outcomes, the report projects enormous economic benefits in terms of life expectancy, reduced disability, and lower health care costs overall.
Lack of diversity in clinical trials may hinder a broader understanding of biology that could benefit the general population, according to the report. A more nuanced understanding of biological processes could lead to innovation and possibly new discoveries from which everyone could benefit.
Diversifying study populations necessarily expands the pool of potential participants. Over half of all Phase I to IV clinical trials are terminated, suspended, or discontinued due to lack of accrual, according to an analysis by GlobalData. Tapping into these underrepresented populations could go a long way in addressing the stubborn challenge of lack of successful recruitment.
Creating inclusive research environments may increase trust in science and medicine. The report calls out vaccine hesitancy as an example. Efforts to persuade pregnant women to take the SARS-CoV-2 vaccine to prevent COVID-19 were stalled due the lack of data, which resulted in high levels of hesitancy among that population.
We still do not have a clear understanding of the current participation of underrepresented populations. Despite the requirement for reporting through the ClinicalTrials.gov portal, we lack sufficient and consistent data-reporting practices. The report attempts to untangle the current situation based on a variety of methodologies.
The report also challenges the assumption that these populations do not want to participate in clinical trials, often due to historical abuses in medical research. According to the report, “the evidence on this issue is clear: Asian, Black, Latinx Americans, and American Indian/Alaska Native individuals are no less likely, and in some cases are more likely, to participate in research if they are asked.”
The report calls out variables that limit participation of these populations. The study scrutinizes individual protocol design to institutional structures, as well as study funders. Even IRBs are not spared the critical review from the authors. According to the report, “IRBs can also present barriers to diverse participation in clinical trials by limiting the types and amount of compensation given to research participants to avoid the impression of coercion or undue influence.”
The report makes a variety of recommendations aimed at addressing this critical disparity in research. Many of them have been addressed in other papers and research conferences: increasing community engagement, building trust, etc. The report strongly recommends establishing a mechanism for reporting to Congress the status of clinical trial engagement. It suggests that the FDA should require a detailed recruitment plan at the time of submission.
The report suggests incentives such as tax credits to sponsors, Fast-Track drug development opportunities, and extended market exclusivity of new drugs or devices. Finally, the report anchors these efforts within the framework of social justice. This framing represents a paradigm shift in the thinking of diversity in clinical trials.
 National Academies of Sciences, Engineering, and Medicine 2022. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Washington, DC: The National Academies Press.
Protecting Privacy of Research Participants When Sharing Data
The National Institutes of Health (NIH) has released two resources to the research community that aim to prepare institutions for the implementation of the NIH Data Management and Sharing Policy, which goes into effect in January 2023.
The first resource, “Informed Consent for Secondary Research with Data and Biospecimens: Points to Consider and Sample Language for Future Use and/or Sharing,” provides points to consider and sample language for investigators to include in informed consent. Researchers can use this material to learn best practices for developing informed consents to facilitate data/biospecimen storage and sharing for future use.
The second document is a draft supplement to the policy, which is open for public comment until June 27, 2022.
Sharing increases the scientific utility of collected data and biospecimens. It also reduces the burden on research participants who participate in different research studies from being asked multiple times to submit data and biospecimens. However, representatives of the NIH acknowledge that investigators and institutions lack guidance on consistent consent language to facilitate secondary research with data and biospecimens. In response, they have published a downloadable guide that provides modifiable sample language that investigators and IRBs can use to assist in the clear communication of potential risks and benefits associated with data/biospecimen storage and sharing.
The guide from NIH addresses only consent for the storage and sharing of data and biospecimens collected during a primary research protocol, for the purposes of future secondary research. Other federal guidelines address the process for approval, storage, and use of the collected data and specimens, both for primary and secondary research.
Here are a few reminders and highlights from the guide:
- Consider the reading level of anticipated study participants. The NIH suggests targeting an 8th grade reading level. Researchers can also consider other methods of providing information, such as explanatory videos.
- Remain diligent when considering vulnerable populations. This can include prisoners, children, or individuals with impaired decision-making capacity. These populations can be vulnerable to undue influence and coercion.
- Understand and be sensitive to cultural or Tribal preferences. Consult with the appropriate constituents and leaders to determine applicable regulations, policies, and cultural preferences or Tribal laws that will need to be taken into consideration prior to storage and sharing of data and biospecimens.
- Review community standards for the consents regarding genomic data. Several resources are available to investigators and institutions, which provide standards for collecting, storing, and sharing genomic data and specimens. This can include the NIH Genomic Data Sharing Policy.
- Be prepared to revise consent documents. As coding and deidentifying technologies advance and capabilities for linking disparate data together evolve, consider the implications for reidentification, privacy, and confidentiality and adjust language as appropriate.
The sample consent language includes four primary components:
Introduction and Description
The Introduction-Description component provides prospective research participants with an introduction to, and description of, the planned storage and sharing of data and biospecimens. It should include the timeframe for storage, if data and biospecimens will retain identifiers, be deidentified, or coded, and how data may be shared.
Voluntary Participant and Withdrawal of Consent
In this section, the consent should clearly state whether data and biospecimen sharing for future research is voluntary or required for participation in the primary study (e.g. repository protocol). This component describes what happens if the participant initially agrees to the storage and sharing of data and biospecimens, and then changes their mind.
Risks and Benefits
This component describes any foreseeable risks and/or discomforts related to the storage or sharing of data and biospecimens. It can include information on how those risks may be managed or addressed by the investigator or institution. Any anticipated benefit from sharing data or biospecimens will also be included in this section. If no direct benefit is anticipated that should be stated.
This section describes if any of the participants data may contribute to the development of products with potential commercial value, and if they may receive compensation.
The sample consent language is voluntary, with no requirements or expectations that it be used. Researchers should carefully select language appropriate for the study and intended participants, and IRBs should ensure that the study’s primary consent meets all applicable regulatory and policy requirements, including federal, state, local, Tribal, and international requirements.
Investigators’ Responsibilities In Contract Lab Services
The FDA recently issued a warning letter to a Florida university’s principal investigator regarding a contract testing lab’s improper handling of data. The letter outlines significant deviations from current good manufacturing practice (cGMP) for active pharmaceutical ingredients (API), including claims that a student analyst falsified data.
Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) outlines cGMP for active pharmaceutical ingredients. Although the university responded previously that the violations were the result of actions of one individual, the FDA countered with additional concerns regarding the safety and quality of the lab.
Investigators and lab managers should take this warning letter as a reminder to conduct their own internal audit to ensure that activities are within the federal guidelines and regulations.
Data Security is Paramount
Investigators must adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs that are analyzed. Data integrity refers to the completeness, consistency, and accuracy of data.
This includes ensuring appropriate access controls and data security.
- Investigators should ensure that everyone with access to databases and systems should have an individual, secure login. Only authorized persons should have access to databases and software. When login credentials are shared, a unique individual cannot be identified through the login and the system would not conform to the cGMP requirements. The FDA requires that system controls, including documentation controls, be designed in accordance with cGMP to assure product quality.
- Raw data should be backed up, and an audit trail should be implemented. An audit trail means a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record.
- Software used to store raw data should be validated. Even if you validate the computer system but you do not validate it for its intended use, you cannot know if your workflow runs correctly.
- Clear policies, procedures, and protocols for analyses should be outlined.
In assessing your own lab’s data security and integrity, it may be useful to ask these questions:
- Are controls in place to ensure that data is complete?
- Are activities documented at the time of performance?
- Are activities attributable to a specific individual?
- Can only authorized individuals make changes to records?
- Is there a record of changes to data?
- Are records reviewed for accuracy, completeness, and compliance with established standards?
- Are data maintained securely from data creation through disposition after the record’s retention period?
Establish a Quality System
Without an adequate Quality Unit (QU) and quality system in place, there is inadequate assurance that controls are implemented to ensure that cGMP testing operations are performing in a state of control. Develop and document detailed policies and procedures, as well as establish the roles that will focus on quality and define their responsibilities.
Ensure Appropriate Staff Training
Training should be regularly conducted and cover, at a minimum, the particular operations that each employee performs and cGMP as they relate to the employee’s functions. This includes any students or interns who may be working in the lab. (Note: CITI Program, a part of BRANY, offers an online GMP course that provides an introduction to GMP for pharmaceuticals and the current U.S. FDA regulations.) The training should be documented.
Failing to comply with these regulations can have significant impact on lab operations. As a result of the FDA’s determinations, the university ceased testing operations for this lab.
Auditing your own internal processes and procedures can go a long way to preventing such a negative impact on operations, not to mention improving the quality and security of data.
Older Adults in Cancer Clinical Trials
While much of the national dialogue about diversity in clinical trials has focused on the inclusion of underserved populations, communities of color, and women, recent FDA guidance turned its attention to the inclusion of older adults — those over 65 years of age — in clinical research. While most cancer trials do not have an upper age limit for exclusion, adults 75 years of age and older are underrepresented in cancer clinical trials.
Cancer can affect anyone at any age, but certain populations are at higher risk than others. Cancer is a disease generally associated with age, with the number of cancer cases projected to multiply due to a rapidly aging U.S. population.
Older patients can sometimes have co-morbidities that may restrict their ability to participate in clinical trials. Eighty percent of adults 65 and over have at least one chronic condition, according to the National Council on Aging. Some eligibility criteria have become commonly accepted over time or used as a template across trials without clear scientific or clinical rationale. The FDA has published guidance on how to broaden eligibility criteria in order to understand the risks and benefits in a population that is more likely to use the drug in real-world scenarios.
Older patients are also more likely to be taking medications, which could impact the pharmacokinetics or effectiveness of a treatment. It can also influence the occurrence of side effects. Even if they are not taking other medications, there may be important differences in efficacy in older adult patients.
The clinical trial population should be representative of the intended population expected to take the drug, should it be approved. In the case of older patients, this can pose a challenge for enrollment. Research sites may consider consulting with geriatricians, geriatric oncologists, social and behavioral scientists with expertise in treating older adults. These experts may have insights and considerations to make it easier to recruit and support these patients.
Older adults may have specific challenges in accessing research sites. For example, urban academic medical centers may be more difficult to reach than community-based settings. Research sites may need to provide accommodations for patients with physical impairments such as limited sight, mobility, or hearing. Caregivers may need additional support.
Where feasible, remote monitoring approaches can offer useful alternatives. But these accommodations should be outlined in the protocol.
Patient-Centered Protocol Design
To facilitate the enrollment of older adults in cancer trials, sponsors may consider flexible approaches to trial design. This may include an open-label safety study that can enroll and analyze an older adult population separately in a parallel arm of a trial. The FDA also suggested stratifying study populations by age.
To support patient-centered clinical trial design, sponsors should consider perspectives of older adults, seeking input from patients and advocacy groups, as well as input from those caring for older adults such as clinicians and caregivers. This information can inform the design of the clinical trials, such as in assuring meaningful endpoints are selected, as well as in the conduct of the trial, such as in facilitating enrollment and retention of older adults.
The FDA advises sponsors and drug developers that “older adults, including those with physiological decline, should be enrolled in all phases of clinical trials when they can be safely and ethically enrolled.” There are several considerations in including these patients. But a successful result can be a better understanding of the benefits and risks of cancer treatments in this population.
 Singh H, Kanapuru B, Smith C, et al., 2017, FDA Analysis of Enrollment of Older Adults in Clinical Trials for Cancer Drug Registration: A 10-Year Experience by the U.S. Food and Drug Administration, JCO, 35:15 suppl, 10009-10009
Three Final FDA Guidance Documents Released to Support Cancer Research
The U.S. Food and Drug Administration (FDA) recently issued three final guidance documents regarding cancer clinical trials. The announcement supports the goals of the so-called “Cancer Moonshot” initiative to facilitate research and advances in cancer prevention, diagnosis, and treatment. Although the guidance is directed primarily at industry sponsors, research sites should be aware of them as they may impact areas of patient recruitment, informed consent, and so on.
Inclusion of Older Adults in Cancer Clinical Trials
While much of the national dialogue about diversity in clinical trials has focused on the inclusion of underserved populations, communities of color, and women, the recent FDA guidance turned its attention to the inclusion of older adults — those over 65 years of age — in clinical research. Older adults are more likely the population that will be utilizing cancer treatments, yet they remain underrepresented in clinical trials.
The guidance encourages the enrollment of older adults in earlier phases of clinical trials. It also includes recommendations for trial design, recruitment strategies, and information collection. It also discusses developing and reporting more discrete age groups to encourage enrollment of this historically excluded population.
Expansion Cohorts: Use in First-in-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics
This guidance provides advice for “First in Human” (FIH) trials, with recommendations for designing and conducting expansion cohort trials. These are trial designs that employ multiple, concurrently accruing subject cohorts, where individual cohorts assess different aspects of the safety, pharmacokinetics, and activity of the studied drug.
The guidance offers considerations for which kinds of interventions are best suited for a multiple expansion cohort design, as well as what information must be included in the new drug application submission. The guidance also addresses issues for institutional review boards (IRBs) and the needed safeguards to protect participants in these expansion cohort trials.
Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics
This guidance document addresses “master protocols.” In contrast to traditional trial designs, where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate more than one investigational drug and/or more than one cancer type in multiple sub-studies.
The goal is for investigators and sponsors to address critical research questions more quickly and efficiently.
Each of these guidance documents include possible implications for IRBs and research sites in the start-up and conduct of oncology clinical trials. Over the next few weeks, we will unpack each of them in a more detailed review.
Using Digital Devices to Collect Patient Data in Clinical Trials
Over the last two years, particularly with the disruption caused by the pandemic, the use of digital technologies in health care has increased exponentially. COVID-19 has had a huge global impact on clinical trials from outright trial cancelations to challenges in recruiting participants. Necessary restrictions on travel and physical contact limited research sites’ abilities to conduct on-site activities, such as patient visits, recruitment, consenting, and diagnostic procedures.
An increased focus on decentralized clinical trials, enabled by digital technologies, has raised concerns among investigators and regulators over the balance between benefits to patients and managing risks to them. Concerns about privacy and usability are also part of the public discourse.
The FDA has recently posted draft guidance regarding “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations.” The guidance, aimed at investigators, sponsors, and other stakeholders, is available for public comment until March 2022.
The draft guidance primarily addresses the use of digital health technology (DHT) to acquire data remotely. This can include the use of wearable technologies and sensors to monitor patient vital signs, or the use of smartphones for self-reporting. Besides clinical and physiological data, other information collected can include psychological, behavioral, or functional data.
Digital health technologies are not limited to hardware. Software platforms can include electronic patient-report outcomes or clinical outcome assessments. Some clinical trials can include a combination of multiple DHTs.
The following are some of the issues that investigators and research sites should keep in mind when evaluating the use of digital health technologies.
Define technology selection criteria
The FDA advises sponsors to ensure that a DHT is fit-for-purpose. In other words, the DHT should be validated and sufficient to support its use and interpretability in the clinical investigation. Issues to consider include:
- The proposed trial population and how the technology may influence participation. This includes education, language, age, and digital literacy. Some participants may need DHTs or computing platforms that support large text, bigger buttons, and foreign language translations to allow for inclusion of diverse populations.
- The design and operation of the DHT should be appropriate for the study participants and their environments. Wearable devices should be comfortable and convenient to ensure participants’ ability to adhere to the protocol. Operational needs include battery life and power supplies, Internet or Wi-Fi access, notifications and alerts in appropriate languages, among others.
Investigators need to evaluate the use of patients’ own devices or computer platforms. There are several advantages and disadvantages to consider. This includes the familiarity of a DHT for a patient and the convenience of using a technology they already have. However, clinical and technical specifications may require a more specialized DHT to ensure precision and accuracy of the data collected.
To ensure that access to participate in trials relying on DHT’s and/or computing platforms is equitable, provisions may also need to be made to make such technology available to potential trial participants who may not have access to such technology on their own.
Validate and verify the technology
The FDA distinguishes the processes of validating and verifying the selected technology to ensure they are “fit for purpose.” Verification ensures that the technology measures accurately and precisely over time. Validation confirms that the technology appropriately assesses the clinical event or characteristic in the proposed participant population.
This initial evaluation process will ensure that the selected DHT appropriately assesses the clinical event or characteristic in the proposed participant population.
Sometimes the DHT manufacturers can provide verification and validation data.
Define clinical endpoints
The protocol should include a description of the clinical endpoints or endpoints measured by the DHT. A precise definition includes the type and timing of assessments, as well as the tools used for the assessments.
Develop a statistical analysis plan
A statistical analysis plan (SAP) supports transparency and reproducibility in research.
Generally, it starts with a description of the data collected during the trial. It provides a comprehensive and detailed description of the strategy, rationale, and statistical techniques to be used to assess the collected data.
Identify and mitigate risks
Sponsors, investigators, and institutional review boards (IRBs) should consider any risks to trial participants associated with use of the DHTs for data collection. These risks can include loss of patient privacy and clinical risks.
Sponsors should address how they will manage or reduce the risk of potential disclosure of identifiable information. This includes understanding end-user license agreements of computing platforms. In some cases the sponsor may need to work with manufacturers to modify the end-use license agreement.
Include risks in informed consent
Informed consent should include a description of the risks, including privacy issues and plans to mitigate such risks. The informed consent process should explain the type of information that will be collected by the DHT and how that information will be used and monitored.
The informed consent process should specify who may have access to data collected through the DHT during or after the clinical investigation, and for how long.
If trial participants stand to incur additional costs, such as data use charges, as a result of using DHTs or computing platforms this information should also be addressed as part of informed consent.
The use of technology to collect patient data in clinical trials holds a variety of promising benefits. But investigators, sponsors and IRBs should be clear in their understanding of the risks and have detailed plans for addressing them.
The FDA’s Digital Health Center of Excellence provides regulatory advice and support to the FDA’s regulatory review of digital health technology
The Clinical Trials Transformation Initiative has developed a suite of recommendations and resources for the use of digital technologies in decentralized trials.
Trends We Are Watching in 2022
As we approach our third year of the global COVID pandemic, we take a moment to reflect on the impact it’s had on health care in general and clinical research in particular. The last two years have laid bare the challenges of equity and access, as well as the importance of leveraging technologies to improve patient experiences and efficiencies.
While the pandemic has generated significant hardships, we believe it has precipitated some necessary advancements in the execution of clinical research. No one knows for sure when the pandemic will become endemic, or what “normal” will look like. However, we will be watching certain activities that we believe will continue.
Here are some trends that started in 2020 that we will watch over the next year.
Decentralized clinical trials
We expect the trend toward decentralized clinical trials, supported by increased use of telemedicine technologies, will continue. Even if administrative staff start returning to the office, many of the efficiencies of remote work are likely to continue in a flexible hybrid work environment.
Clinical trials will probably continue to leverage remote patient monitoring, using tracking devices or smartphones. Patient visits may occur via video conferencing rather than requiring them to come to a clinic or facility. This may allow researchers to expand their ability to recruit patients from further geographic distances. It will also require re-training of research staff to make the most of these technologies while ensuring patient privacy.
Diversity in clinical trial participants
In 2021, the public dialogue about diversity and inclusion in clinical trials increased. The FDA encouraged researchers and sponsors to develop and adopt mechanisms for increasing the participation of underrepresented groups in their clinical trials. This includes expanding eligibility criteria and adopting adaptive clinical trial design methodologies.
We anticipate hearing more this year about addressing the needs of specific populations, including ethnic groups, children, women, and LGBTQ communities.
Other industries have seen significant staffing impacts due to COVID. While media attention is focused on the so-called “Great Resignation,” much of the disruption has, in fact, been due to increases in the number of cases of COVID and isolation protocols for those who have been exposed.
Research organizations need to plan for this continued flux in their staffing levels in order to sustain projects and ensure continuity.
Accelerated Clinical Trials
The record-breaking speed by which COVID vaccines and treatments have been developed, reviewed, approved, and deployed have inspired researchers to consider how to translate the lessons learned to other clinical trials in other diseases. Some options may include simplifying protocols or leveraging observational research with “big data” mining.
Over the two years, we have seen increased attention on patient-focused approaches to clinical trials that take a variety of factors into account. The health care field has been at the fulcrum of the challenges wrought by COVID. But clinicians and their teams have also demonstrated enormous resilience and innovation. We will continue monitoring the landscape and identifying winning strategies that not only make clinical trials more efficient, but that also continue to protect human subjects.
Diversity in Clinical Trials — Patients with Disabilities
The public conversation regarding equity, access, inclusion, and diversity in clinical trials covers a wide spectrum of underrepresented communities, including race, ethnicity, socioeconomic status, sexual orientation, and gender identity. One population that receives less attention are patients with physical or cognitive disabilities. Including patients with cognitive disabilities in clinical trials poses special challenges. Among the challenges is the ability to assess the patient’s capacity to consent to participation in a research trial, or, if allowable under state or local law, allowing a legally authorized representative (LAR) to consent on behalf of a patient that is unable to consent for themselves. Whenever possible, the patient’s assent should be obtained in addition to consent from the LAR.
Granted, many clinical trials specifically evaluate drugs to treat patients with debilitating diseases, such as multiple sclerosis or Parkinson’s disease, that cause disability. Indeed, patient function and changes in disability are common primary or secondary endpoints in some Phase III drug trials. In other research, such as on learning disabilities, researchers measure the impact of non-drug interventions on specific patient populations.
What are the considerations for trials that do not specifically address a disability or impairment? How can institutions include these patients in the overall scope of recruitment and inclusion? How can investigators write protocols with inclusion or exclusion criteria that take into account the diversity of the study population? How do IRBs set policies and criteria for assessing risk versus benefit?
In 2018, as mandated by the FDA Reauthorization Act (FDARA), the FDA held a public meeting to discuss topics related to eligibility criteria in clinical trials, including:
(1) the rationale for, and potential barriers created by, inclusion and exclusion criteria;
(2) the benefit to appropriate study populations from trials with alternative designs;
(3) barriers to clinical trial participation;
(4) clinical trial designs that increase trial population diversity;
(5) how changes to trial inclusion and exclusion criteria could impact clinical trials; and
(6) how changes to eligibility criteria may impact the complexity and length of clinical trials.
Discussions at the public meeting informed subsequent guidance issued by the FDA that addressed several topics, including:
Broaden eligibility criteria
Some eligibility criteria have become commonly accepted over time or used as a template across trials, sometimes excluding certain populations from trials without strong clinical or scientific justification. Eligibility criteria should be carefully considered and not automatically defined by past practices.
Investigators should consider eligibility criteria that will result in a representative sample of the population for whom the treatment is intended. Likewise, exclusion criteria should be based on the safety of trial participants or the study objectives. For example, the risk to patients with certain advanced comorbidities require that they may be excluded. However, patients with the same, but less advanced, diagnosis may be included.
Likewise, exclusion criteria from Phase II trials might not be relevant in Phase III studies, when sponsors have a better understanding of adverse events, toxicity, and other factors.
Leverage adaptive trial design
An adaptive trial design is one that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity.
An adaptive design can start with a narrow population if there are concerns about safety and can expand to a broader population based on interim safety data from the trial that provide support for doing so.
IRBs must be particularly vigilant in reviewing adaptive trial designs. They should evaluate them based on patients’ safety and scientific validity, as well as whether the change reflects the target population.
A trial requiring participants to make frequent visits to specific sites may result in added burden for participants, especially disabled and cognitively impaired individuals who require transportation or caregiver assistance. Some patients with disabilities may require reasonable accommodations, such as physical access or sign language interpreters.
Institutions should consider mechanisms to ease these burdens. Examples of modifications include:
- Reducing the frequency of visits to those essential for monitoring safety and efficacy
- Allowing for flexibility in visit windows
- Including electronic or remote monitoring via video conference, email
- Considering digital health technology tools to monitor patients
- Hiring medical staff to conduct home visits for blood draws and other monitoring
Research budgets may include financial reimbursements for expenses associated with costs incurred by participation in clinical trials, such as travel or lodging expenses. The FDA does not consider reimbursement for reasonable travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.*
Incorporate patient-focused practices
Investigators and researchers can implement strategies for public outreach and education. They can engage with patient advocacy groups, medical associations, community-based advisory groups, and other organizations to identify opportunities for inclusion. These groups can also provide input at the protocol design stage by offering feedback on what elements of the protocol may discourage participation. These valuable insights into the challenges and burdens of patients with disabilities, as well as their caregivers, can inform improvements to the protocol.
Broadening eligibility criteria and minimizing barriers to participation in clinical trials can ensure that the study population is more representative of the community. This must be balanced with the obligation to also protect vulnerable populations and those who may not have the capacity to understand the risks and/or potential benefits associated with research. This, in turn, can improve the quality of the data collected and the research overall. With a careful eye toward evaluating the benefit versus the risk to patients with disabilities, IRBs play an important role in discerning this balance.
* See the information sheet guidance for institutional review boards and clinical investigators Payment and Reimbursement to Research Subjects (January 2018). See also 21 CFR 50.20.
The Great Resignation — Managing the Impact on Research Teams
Among other things, 2021 will be known as the year of The Great Resignation, or in many sectors, the great retirement. Record numbers of employees left their jobs. Nearly four and a half million Americans left their jobs in September 2021, the highest number on record since the Bureau of Labor Statistics began collecting data 20 years ago. The numbers show a 40 percent increase over the same period in 2020.
The healthcare sector has not been spared. According to the report, 589,000 U.S. workers resigned or retired from health care and social assistance positions. A children’s hospital in Ohio recently put out a call for clinical volunteers to help support staffing shortages. A study in Utah in April that tested the sentiments of nearly 28,000 University of Utah Health system clinical and non-clinical faculty, staff and trainees found that 20 percent of respondents, 1 in 5, are considering leaving their professions.
Economists and pundits are untangling the possible reasons for this massive change in the labor market. Some suggest The Great Resignation is driven by massive burnout among workers. Others point to stagnant wages, lack of career growth opportunities, and challenging work conditions. Yet others suggest that employees who have been working from home simply do not want to return to the office and prefer the flexibility offered during the pandemic.
The trend may continue. A recent Gallup survey found that 48 percent of the working population in the United States is actively job searching. Studies show that the trend is driven by mid-career employees — those between 30 and 45 years old as well as those close to retirement age that decided to retire after the height of the pandemic. This can suggest a loss of critical experience and expertise, in addition to the drop in engagement and productivity.
Recruiting, hiring, and training new research staff is expensive and time-consuming. This effort may impact the ability of research sites’ to manage current clinical trials or even start new trials in 2022. The disruption in staffing also may pose risks, since much of the work requires a fine-tuned attention to detail that may be lost as staff including coordinators, research nurses, and principal investigators transition to roles outside of research or move to other organizations.
To mitigate these risks, leaders must address employee disengagement on multiple fronts — long-term and short-term. In the long term, research leaders need to evaluate how to retain and engage experienced workers to minimize turnover. In the short term, workers must be protected from overwork and potential burnout, and offered the opportunity to engage in meaningful work with flexibility.
To achieve this, research administrators and leaders can consider these strategies:
- Increase learning opportunities — Beyond the required training and certifications for clinical research coordinators and other staff, leaders should provide additional online learning opportunities. A June 2021 survey with Amazon, Gallup found that 57 percent of U.S. workers want to update their skills and 48 percent would consider switching jobs to do it.
Advanced training and “upskilling” can include courses in project management for clinical trials; preventing and identifying misconduct and noncompliance; financial management of clinical trials; subject recruitment and retention; statistics and data management of clinical trials; and specialty areas including regulatory compliance.
- Cultivate career development — The same Gallup study showed that the primary reason people change jobs is for career growth opportunities. Training can position early-career staff for additional responsibilities, which then provides research sites with a deeper bench of talent for advancement.
Managing clinical trials requires many administrative tasks that, while important, may be less professionally fulfilling. Having a clearly communicated path for career growth and advancement can incentivize employees to stay.
- Create flexible work environments — Starting and running clinical trials requires a high degree of staffing flexibility as workloads shift. Outsourcing the administrative burden can enable site staff to focus on strategic needs while filling in short-term gaps. The result can be more efficient resource management and consistency in research infrastructure.
The Great Resignation of 2021 shows no signs of slowing in the new year. Research sites must create and nurture environments for employee career growth and engagement to remain competitive.
Clinical Trials in Children
Pediatric clinical trials for the COVID-19 vaccine have started in the United States for children as young as six months. The COVID-19 vaccine made by Pfizer-BioNTech is already authorized for emergency use in anyone 12 and older in the U.S., Canada, and the European Union. The company is seeking FDA approval for use of the vaccine for children over five years old.
Many drugs prescribed to children have not been thoroughly tested in children through adequate, well-controlled, and validated clinical trials. Before the FDA initiated a pediatric program, only about 20 percent of drugs approved by the FDA were labeled for pediatric use.
The historical lack of pediatric clinical trials stems from a variety of reasons.
Running a clinical trial in children has special considerations, particularly since children have specific needs. Among those needs are the logistics of carrying out the studies. You need child-friendly environments, from age-appropriate equipment and medical techniques to pediatric specialists who are sensitive to a child’s fear, according to an article on the FDA website. Some procedures that may be easier for adults can pose challenges for children, such as on-demand urine samples or blood draws.
There are also clinical concerns, such as appropriate dosing and children’s biology, metabolism, and development. Children may metabolize active ingredients differently. Simply reducing a dose is often not sufficient to determine efficacy and safety of a drug in children. Studies must use appropriate formulations for each age group.
Increasing Pediatric Trials
The Pediatric Research Equity Act (PREA) gave the FDA the authority to require pediatric studies in certain drugs and biological products. A sponsor who will be submitting an application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial Pediatric Study Plan (PSP) within 60 calendar days after the date of the end-of-Phase 2 meeting with FDA (unless FDA and Sponsor agree to another time). Sponsors who do not meet this requirement risk receiving a Non-Compliance Letter under 505B(d)(1) of the Federal Food, Drug, and Cosmetic Act.
Aside from the rebuke of a non-compliance letter, the Act also incentivizes sponsors and investigators to include pediatric arms in their clinical trials. Sponsors receive certain protections, such as marketing exclusivity, if they include studies in children in their drug development.
For antibiotics and drugs that are already on the market, the FDA offers mechanisms through the National Institutes of Health (NIH) to fund pediatric studies. The NIH, in consultation with the FDA and other pediatric experts, publishes an annual Best Pharmaceutical for Children Act (BPCA) Priority List of Needs in Pediatric Therapeutics. This list must include drugs for which pediatric clinical trials are needed but funds are not available to support such trials.
Since the passage of PREA, there has been a dramatic increase in research that has resulted in drug labeling additions for over 80 drugs. As a result, physicians have more accurate drug dosing parameters.
IRB Review of Pediatric Trials
The federal regulations related to FDA-regulated products (21 CFR 50.50 to 50.56) outline requirements that institutional review boards (IRB) must follow to ensure additional safeguards are in place for children who will be involved in research.
In assessing the risks and potential benefits, an IRB should consider the circumstances of the children to be enrolled in the study. For example, an IRB should consider the health status, age, and ability to understand what is involved in the research. The IRB should also review the degree of risk and potential benefits to the individual child, other children with the same disease or condition, and society as a whole.
For any protocol involving children, the IRB must determine which of the following three categories of research apply to that study, if any. The IRB must also determine whether one or two parent signatures are required, although typically two parent signatures are only required for the third category.
Research not involving greater than minimal risk to the children.
To approve this category of research, the IRB must make the following determinations:
- the research presents no greater than minimal risk to the children; and
- adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.
Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual child subjects involved in the research.
To approve research in this category, the IRB must make the following determinations:
- the risk is justified by the anticipated benefits to the subjects;
- the relation of the anticipated benefit to the risk presented by the study is at least as favorable to the subjects as that provided by available alternative approaches; and
- adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.
Research involving greater than minimal risk and no prospect of direct benefit to the individual child subjects involved in the research, but likely to yield generalizable knowledge about the subject’s disorder or condition.
In order to approve research in this category, the IRB must make the following determinations:
- the risk of the research represents a minor increase over minimal risk;
- the intervention or procedure presents experiences to the child subjects that are reasonably commensurate with those inherent in their actual, or expected medical, dental, psychological, social, or educational situations;
- the intervention or procedure is likely to yield generalizable knowledge about the subject’s disorder or condition which is of vital importance for the understanding or amelioration of the disorder or condition; and
- adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.
If the IRB believes that the research does not meet the requirements for any of the above categories, but finds that it presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, it may refer the protocol to the Commissioner of FDA for review.
Children who are part of clinical research deserve additional protections. Several U.S. regulatory agencies have developed mechanisms and guidance both to encourage additional research and to protect the children in that research. IRBs that may be reviewing protocols that include pediatric patients should be up to date with any requirements or additional guidelines.
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.
BRANY Welcomes New Hires Just in Time for Increased Research Demand
BRANY announced several new hires as almost 50% of respondents in a recent BRANY survey report they expect the level of clinical trial activity to return to pre-pandemic levels by 2022. The influx of new talent is aimed to ensure BRANY continues to serve the evolving needs of our customers looking to restart or open new clinical trials amid the ever-shifting COVID-19 environment. This comes at a time when respondents report the two biggest barriers to returning to research are securing sufficient funds (15%) and securing appropriate staff (25%) – highlighting the need for additional support among the field.
New BRANY Team Members
- Jerard Bellamy rejoined BRANY as a Budget Associate for the Clinical Trials Activation Team, responsible for developing study budgets in accordance the research protocols, and applicable research charge masters ensuring all research procedures are appropriately captured.
- Michael Brown rejoined BRANY as a Client Services, Sales Director focusing on IRB and IBC services. Michael is responsible for engaging with decision makers at pharmaceutical and biotech companies, AMCs, hospitals, and universities with a goal of expanding BRANY IRB and IBC services across the U.S.
- Shayla Cosgrove joined the Clinical Trials Activation Team as a Budget Associate, responsible for developing and negotiating budgets for clinical trials in accordance with industry standards and best practices.
- Farnaz Imtiaz joined as a Junior Associate IRB Coordinator, responsible for processing research applications received by BRANY IRB.
- Farzana Mahamud joined BRANY as an IRB Meeting Specialist, responsible for screening incoming IRB and IBC submissions, gathering all materials required for review, circulating meeting materials to committee members, and facilitating meeting activities for both BRANY IRB and IBC.
- Jennifer Mosby joined BRANY as an IRB Associate Coordinator, responsible for screening and coordinating the IRB review of new and ongoing research studies ensuring federal regulations compliance.
- Giselle Rodriguez joined the BRANY finance team as a Research Billing Analyst, responsible for invoicing, payment processing, and collection activities associated with research studies.
Principal Investigators’ Responsibilities to Post Clinical Trial Information
The FDA recently issued a notice to a California-based principal investigator regarding non-compliance with the requirement to submit clinical trial results information to the ClinicalTrials.gov data bank. The requirement, part of the Food and Drug Administration Amendments Act of 2007 (FDAAA), was designed to improve clinical trial transparency.
Although the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11) went into effect in 2017, the agency did not issue any Notices of Noncompliance until this year. This latest notice represents the first letter to an individual principal investigator, rather than a sponsor.
The responsible party of a clinical trial can be an academic institution, hospital, private company, a government research organization, or an individual principal investigator.
If a principal investigator is deemed the “responsible party,” then he or she is responsible for complying with this requirement. Typically the responsible party is the sponsor, but a principal investigator of a clinical trial can be the responsible party if he or she:
- is responsible for conducting the trial,
- has access to and control over the data from the clinical trial,
- has the right to publish the results of the trial, and
- has the ability to meet all of the requirements for the submission of clinical trial information
A responsible party for an FDA applicable clinical trial is required to submit to the ClinicalTrials.gov data bank certain results information for the clinical trial, within one year after the primary completion date of the applicable clinical trial. Certain exceptions include situations in which the responsible party has submitted:
- a certification of delay
- a request for an extension of good cause
- a request for a waiver of the requirements for submission of results information
A few things about this notice are worth noting in terms of what is considered sufficiently complying with the requirements.
Determine if a protocol meets the definition of an applicable clinical trial
The FDA has developed a to help responsible parties evaluate whether a clinical trial is an applicable clinical trial (ACT).
Notify Research Participants
Informed consent forms for applicable clinical trials must also advise research participants about the requirement to post clinical trials on ClinicalTrials.gov. A statement such as the one shown here can be included in the informed consent document:
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time.”
Know the requirements for submission
The regulation in 42 CFR 11.48(a)(5) requires the responsible party to submit data in a tabular format summarizing:
- participant flow
- demographic and baseline characteristics
- primary and secondary outcomes,
- results of any scientifically appropriate statistical tests
- adverse event information
In addition, the rule requires the submission of the full protocol and statistical analysis plan (if a separate document), and all amendments that have been approved by an institutional review board (IRB).
Published results in a manuscript are not sufficient to meet the requirements for submission of clinical trial results information to the ClinicalTrials.gov data bank.
Understand the deadlines
The responsible party must register the applicable clinical trial on ClinicalTrials.gov within 21 days after the first human subject is enrolled and submit certain summary results information for those trials, generally no later than one year after the study’s completion date unless a deadline extension is obtained.
Analysts and observers say that the latest letters indicate a willingness of the FDA to “up the ante” on enforcement of the Final Rule. Non-compliance can mean a hefty monetary penalty. Violators are subject to a civil monetary penalty of up to $10,000. Investigators and research institutions should refresh their training regarding their responsibilities in order to avoid noncompliance.
CITI Program offers a webinar for Investigators and Institutions on “Building a ClinicalTrials.gov Compliance Program.” Learn more here.
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.
Coverage Analysis for Investigational Device Exemption (IDE) Studies
A Medicare coverage analysis (MCA) for clinical trials evaluates which tests, procedures, and interventions will be associated with a clinical trial. This analysis results in a budget and plan for invoicing third party payers and sponsors. Clinical trials for devices differ from interventional trials for drugs in a few key ways that can impact the process of conducting a coverage analysis.
While drug trials often involve a local review by the institution to document the qualification of a clinical trial, device trials with an FDA letter dated effective January 1, 2015, are reviewed at the national level by CMS. Prior to this change, devices with an FDA letter dated prior to January 1, 2015, sponsors and sites had to wait for IRB approvals and fully executed agreements in order to submit documents to the local Medicare contractor.
Medicare authorizes payment of the routine costs of care furnished to its beneficiaries in certain categories of Investigational Device Exemption (IDE) studies. However, there are a few items that Medicare excludes. These includes costs for items:
- paid for by the sponsor
- identified as free in the informed consent document
- not ordinarily covered by Medicare
- solely to determine trial eligibility or for data collection or analysis
The CMS approval process applies to category A and B trials. The category of the device, as assigned by the FDA, determines what is reimbursed by Medicare.
- Category A devices are experimental or novel. Medicare will cover only the routine costs of care, but not the device itself.
- Category B devices are non-experimental, or a similar device may already be in the marketplace. Medicare may cover the costs of care and the device.
To identify the “routine costs of care,” it is important to understand the protocol in detail. Devices may require surgical interventions that include a hospital stay, thus complicating the billing process. Analysts must review the ICD billing codes that may be referenced, including both hospital and professional fees.
To be considered for coverage, CMS requires documentation that covers similar issues as a drug intervention trial. CMS requires the submission packet to include:
- Request letter that describes the scope and nature of the study
- Complete FDA approval letter for your Category A or B IDE
- IDE study protocol that includes descriptions CMS wants to see:
- Method and timing of release of results on all prespecified outcomes, including release of negative outcomes and that the release should be hastened if the study is terminated early
- How Medicare beneficiaries may be affected by the device under investigation
- How study results are or are not expected to be generalizable to the Medicare beneficiary population
- Institutional Review Board (IRB) approval letter
- The National Clinical Trial (NCT) number
- Any supporting materials
The sponsor may sometimes submit the packet to CMS for reimbursement. After that, the investigator or study site should be in contact with their Regional Medicare Administrator (MAC) to receive acknowledgement of receipt and receive further information on obtaining billing and coding information.
CMS does not provide detail about which clinical items are approved for reimbursement. Despite receiving CMS approval for an IDE study, sites are accountable for negotiating the contract with the sponsor and for billing appropriately. An accurate and detailed coverage analysis ensures correct billing and avoids costly financial errors. More importantly, it reduces the risk of non-compliant billing, which can have significant negative repercussions. The analysis is an essential component of a study start-up process and conducting it in a timely way can avoid start-up delays.
Medicare Coverage Related to Investigational Device Exemption (IDE) Studies (CMS)
Evaluating an Investigator’s Qualifications
Research related to COVID-19 has increased awareness in the community about the role of the institutional review board (IRBs) to protect the rights and welfare of research participants. The regulations and guidelines in place to ensure the safety of research participants cover a wide range of areas that need attention. In addition to evaluating a protocol, IRBs have additional responsibilities to ensure the safety of research subjects. One of the areas for consideration is the background of the principal investigator, as well as the qualifications and training for some research staff.
The FDA says that IRBs must consider the qualifications of the investigators in reviewing a protocol. While the guidance clearly puts the responsibility of identifying appropriately qualified investigators and study sites on the shoulders of study sponsors, IRBs have a responsibility to evaluate an investigator’s qualifications in the interest of protecting study subjects.
This evaluation may be relatively simple and straightforward, or it may entail a more involved assessment depending on a variety of factors, such as familiarity with the investigator.
In many cases, the IRB may have previous experience with an investigator or institution that would allow the IRB to readily determine that the clinical investigator is appropriately qualified to conduct and supervise the proposed research. Familiarity may be a double-edged sword, however. The IRB should have an objective assessment procedure rather than relying on familiarity with the investigator. An assessment process may include some or all the following documentation:
- an updated curriculum vitae of the investigator and, if required, sub-investigators, and other necessary study staff that includes education, training, and experience
- verified professional associations
- verified medical licensure and/or certifications
- relevant publications authored or co-authored by the investigator
- investigator’s training in good clinical practice, HIPAA, Conflict of Interest, informed consent process, proper recruitment methods, and research ethics
Some research protocols may involve higher risks, vulnerable subjects, or novel technologies. In these cases, the IRB may also assess:
- the investigator’s experience in conducting similar studies, demonstrated by recent presentations or publications, and
- prior clinical experience with study intervention or study-related procedures
As part of the investigator screening process, IRBs may routinely check the FDA’s Web site for information related to clinical investigator inspections, Warning Letters, disqualification proceedings, and debarments. This information is publicly available.
To ensure that investigator qualifications are consistently assessed, even when the IRB is familiar with the investigator, IRBs will often have a procedure or checklist in place for evaluating and documenting investigator qualifications. This would apply to the principal investigator as well as the entire research team.
Addressing Burnout Among Clinical Research Staff
In March 2019, we published an article addressing the threat of burnout among clinical research coordinators. A year later, research centers were scrambling to close amid lockdowns. Clinical trials were paused as resources shifted to caring for the surge of patients with COVID-19 in hospitals. Health care providers, including clinical research professionals, were thrust into the front lines of fighting a global pandemic.
Experts believe the pandemic has exacerbated a pre-existing burnout crisis. With uncertainty about job security, and myriad issues relative to working remotely, or returning to offices and workplace safety, job stress is reaching a fever pitch. Issues of mental health in the workplace have gained increased media attention over the last year. Last month, the Department of Health and Human Services (HHS) announced they were earmarking $103 million from the pandemic relief fund to address burnout among health care workers.
The journal Health Policy published a report earlier this year that identified burnout as the driving factor behind nurses quitting their jobs, even before the pandemic. According to the study, over a third of them said they left because of burnout, citing stressful work environments and inadequate staffing. Among healthcare works, a variety of factors associated with COVID-19 correlated with significant mental health impacts.
Burnout may have implications for quality of care and patient safety. Several tools, developed specifically for those who work in health care, can help individuals, managers and teams navigate the challenges of working in unpredictable and stressful environments. We offer this collection of resources for our community.
Stanford Medicine WellMD & WellPhD Center works to advance the well-being of physicians and biomedical scientists.
Reenergizing the Workforce: How Leaders Can Overcome Pandemic Fatigue
A paper published by McKinsey & Company
How to Cope with Stress and Build Resilience
A guide for health care providers by the CDC.
Signs and Symptoms of Burnout
A guide by the Institute for Quality and Efficiency in Health care.
Managing Fatigue in Times of Crisis
By the U.S. Department of Health & Human Services
Strategies to Support Health and Well-Being of Clinicians
A toolkit for clinicians and clinical leaders by the National Academy of Medicine
How to Measure Burnout Ethically and Accurately
An article by the American Association of Physician Leadership that outlines the Maslach Burnout Inventory, a scientifically developed measure of burnout used widely in research studies around the world.
Pandemic Burnout in Academia
This article in the journal Nature exams how the pandemic is taking its toll on scientists.
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
Identifying Social Determinants in Clinical Trial Screening
Social determinants of health (SDoH) are conditions in the places where people live, learn, work, and play that affect a wide range of health and quality-of life-risks and outcomes. Collectively, they contribute significantly “to the social patterning of health, disease, and illness,” according to the CDC.
Examples of these social determinants include safe and affordable housing, access to education, public safety, availability of healthy foods, local emergency/health services, and environments free of life-threatening toxins. A study showed that nationally, patients faced an average of 7.2 out of 22 social risks. The most common SDoH risks among all three cohorts in the study were limited English proficiency, less than a high school education, lack of insurance, experiencing high to medium-high stress, and unemployment.
If SDoHs have an impact on clinical outcomes, then it stands to reason that they may also have an impact on clinical trial outcomes. A study by Yale University in 2019 demonstrated this phenomenon. Their study, published in the Journal of the American Heart Association, compared outcomes in an interventional study (ALLHAT) comparing medications for hypertension. Their results showed that patients who received their care in low-income areas had vastly different outcomes than patients in higher income areas. “Despite standardized treatment protocols, ALLHAT participants in the lowest‐income sites experienced poorer blood pressure control and worse outcomes for some adverse cardiovascular events, emphasizing the importance of measuring and addressing socioeconomic context,” according to the authors.
Despite these findings, and general acceptance of the role of social determinants, these factors are rarely reported in clinical trial results, according to a JAMA study published in May of this year.
Clinicians do not agree on whether to screen for social determinants. They offer various reasons for this resistance. A survey conducted by the Robert Wood Johnson Foundation found that four out of five physicians do not feel confident in their capacity to meet their patients’ social needs, and they believe this impedes their ability to provide quality care. Physicians do not have the time or sufficient staff support to address patients’ social needs, according to the study.
While the FDA has offered guidance to sponsors regarding the collection of ethnicity data in clinical trials, there is no specific guidance on collecting information about SDoHs.
The recently announced CURES 2.0 Act, which includes provisions for creating a new research agency, Advanced Research Projects Agency for Health, or ARPA-H, also generally calls for increased diversity in clinical trials and the collection of so-called “real world data.” Social and economic conditions can negatively impact willingness and ability to participate in research. Recognition and understanding of SDoHs may help address and overcome barriers to minority participation in research. But the proposed law does not specifically address the collection or analysis of SDoHs as part of clinical trial screening.
For clinician-investigators interested in including this information about study participants, a variety of screening tools are available. The American Academy of Family Physicians, American Academy of Pediatrics, and the National Association of Community Health Centers all offer these instruments online. These may require additional training for research staff or adjustments to workflow in the screening process. An article published in 2020 suggested certain data points may act as surrogates for collected detailed information about SDOHs. The American Association of Family Physicians developed a checklist for primary care practices to prepare for screening SDOHs.
There is a national movement to understand the barriers to diversity in clinical trials, and the impact of social determinants in health outcomes. While there are no specific requirements to include this data in the screening process, clinician-investigators can include this in their protocols to gain a clearer understanding of these factors in their trial endpoints.
Be Prepared for an FDA Audit
An FDA audit or inspection can occur at any time, and sometimes with very little advance warning. The FDA conducts both announced and unannounced inspections of clinical investigator sites, typically under the following circumstances:
- to verify the accuracy and reliability of data that has been submitted to the agency;
- as a result of a complaint to the agency about the conduct of the study at a particular investigational site;
- in response to sponsor concerns;
- upon termination of the clinical research site;
- during ongoing clinical trials to provide real-time assessment of the investigator’s conduct of the trial and protection of human subjects;
- at the request of an FDA review division; and
- related to certain classes of investigational products that FDA has identified as products of special interest in its current work plan (i.e., targeted inspections based on current public health concerns).
News headlines that attract the most attention tend to reflect serious allegations of fraud or negligence. The tendency may be to breathe a sigh of relief that such egregious offenses could “not happen here.” However, it’s the smaller, less obvious infraction that can slip through the cracks and cause serious headaches for investigators and their staffs. For example, if an inspector finds an issue with one clinical trial, the investigation may extend to your other trials.
FDA audits are usually just a routine procedure, but they can elevate the stress in a research office. Audits, whether in person or virtual, can last days, and questions are likely to come up.
As part of BRANY’s service to clients, a member from our quality team can work with research coordinators and investigators to organize documents for an efficient and orderly FDA review. There is much that the research site can do, however, to ease the process.
A review of research site audits we have conducted over the last several years highlights a few areas in which research staff can protect themselves before and during a trial.
Here are a few tips for being audit-ready at any moment.
Start with solid documentation. Starting on a strong foundation of detailed documentation will prepare your team for an inspection. Even if there are issues that come up during a trial, accurate and up to date documentation will outline how those issues occurred and were managed.
Organize each study topic. One of the most time-consuming efforts for research staff is organizing and properly labeling the materials. But this is an essential step in making information easily referenced and accessible.
We do not recommend relying on your electronic medical record to stand on its own. Because there are so many applications used by different institutions, regulators and auditors are not likely to want to navigate the software to find the information. The impetus is on the research office to extract and organize the information.
Refresh your memory. If the FDA does request an audit, take time review all the cases and review any issues that may have come up during the life of the trial. This will reduce your anxiety and risk of fumbling for answers should you be questioned.
Track any deviation from the protocol. Even if a sponsor approves a deviation from the study protocol, you are still required to log and report it to the IRB. Some changes can seem inconsequential. For example, a patient reschedules an appointment, so the follow-up occurs outside the defined timeframe. It must be documented and submitted. No deviation is too small for documentation and submission to the IRB. Remember to review monitoring reports for cited deviations and report to the IRB as required.
Additionally, it can also be beneficial to use a log to track concomitant medications, and adverse events.
Update credential and license information. For long-term studies, it’s important to review and update CVs and licenses in the regulatory binder. Review investigators’ medical licenses and update the documentation if they have expired.
Likewise, if your organization is using its own labs for processing specimens, it is important to update any CLIA or other certification documentation. Typically, lab certifications expire annually.
If you are packing and transporting any infectious agents, such as lab specimens, your personnel must receive training. The International Air Transport Association (IATA) has training for compliance in dangerous goods transportation. Anyone who collects, packs or ships these materials should be trained and certified; this must be documented in the regulatory binder.
Monitor your Delegation of Authority Log. If you add a new investigator to the trial, or hire a new research coordinator or study nurse, you must document the addition of any key personnel in your Delegation of Authority Log and have tasks appropriately delegated. This information must also be submitted to the IRB and confirm the key study personnel are IRB approved prior to performing key study procedures.
Conduct periodic internal reviews. With busy schedules, it can be tempting to wait for monitors to flag concerns. But it’s important to be proactive. Conducting a spot check every six months and a more detailed annual audit may protect you from panicked scrambling in the days before an announced FDA visit.
Being prepared for an audit does not mean hours of review. The secret of success is to keep regulatory binders up to date including sponsor correspondence, and IRB approval letters and correspondences, and to report changes and updates to the research to the IRB in a timely manner. If you doggedly track the seemingly small items throughout the course of a study, you will be in a good position to succeed in an FDA review.
Fair Market Value
One of the most critical first steps in preparing to launch a clinical trial is the development of a budget that covers expenses and compensates the research site. The budgeting process can be complex and requires detailed review of the protocol and a methodical line-by-line attention to detail. A properly negotiated budget ensures that a research site is reimbursed for all direct costs for conducting the study, as well as indirect administrative and overhead costs.
The challenge is in determining what is a “fair market value” (FMV) for those services. The U.S. Department of Health and Human Services’ Office of Inspector General (OIG) Guidance for Pharmaceutical Manufacturers provided initial guidelines for fair market value in 2003. The guidance stated that compensation must be “fair market value for legitimate, reasonable, and necessary services.” Since then, a variety of other federal regulatory agencies have also developed rules and laws regarding the compensation of investigators, clinicians, and medical facilities. While compliance with these standards is a mandate, the process of defining FMV may still be opaque.
Institutions at a Disadvantage
In determining the budget, research analysts or those developing the budget often rely on charge masters from each clinical department to set fees for services delivered during a clinical trial. On the other hand, sponsors use algorithms and databases to define so-called “fair market value.” The sponsors’ approach can put some institutions at an unfair disadvantage if the fair market value is determined to be below what the institution typically charges for the service.
The potential for dissonance between the two approaches can impact both large academic institutions and smaller research sites. Fair market value for one institution may not represent fair market value for another. For example, if an institution charges $2,000 for a procedure and another one charges $1,000, a sponsor may average them to $1,500. The institution that charges the higher fee may receive less than their estimated research budget on that service or procedure. On the other hand, a research site might not have access to a charge master or well-established methodologies for establishing their own fair market value and, therefore, have less insight to the real cost of conducting those services. The sponsor’s fair market value determination may well be below what the institution needs to cover its own costs, therefore they may operate the clinical trial at a financial loss.
Beyond the Budget: Ensuring Compliance
An accurate fair market value assessment also requires familiarity with federal regulatory guidelines and laws. Several regulations from a variety of agencies can influence how a research site sets a fair market value. They include:
- US Sunshine Act
- False Claims Act
- Stark Law for anti-kickback statutes
The Centers for Medicare & Medicaid Services (CMS) recently clarified key valuation terms for physician services. This may have implications for how physician-investigators approach their budgeting process. In addition to services, budgets need to account for administrative costs.
The CMS defines FMV as: “The value in arm’s‐length transactions, consistent with the general market value.” The final rule, published earlier this year, defines general market value as “compensation that would be paid at the time the parties enter into the service agreement as a result of bona fide bargaining between well-informed parties that are not otherwise in a position to generate business for each other.”
Creating Defensible Methodologies
There are several approaches to valuating compensation: based on projected income, costs, or the overall market. Each requires a careful analysis, and some approaches may not be appropriate for determining a clinical trial budget.
When evaluating budget line items, research professionals often gauge fair market value against the prevailing market rates. That means the budget reflects the analysis of recent similar transactions and may be based on industry or specialty percentile rankings. This can be problematic if the assessment is not done correctly. For example, the analyst should have a large enough sample size of comparable services against which to benchmark a cost.
Institutions should develop and adhere to a consistent and transparent methodology for evaluating fair market value. To help ensure adherence to federal guidelines, mitigate risks of non-compliance, and shore up a defensible FMV, we advise documenting the sources of information used in developing the budget. For example, what kind of database or charge masters do you use for assessing market rates for services? If you are estimating the time it takes to do a task, such as conducting an informed consent, be sure to have staff track and document their hours over a period of time so you can use this data collected to substantiate the rate utilized.
Of course, comparing your institution’s FMV against a community or regional benchmark is difficult, if not impossible, for individual research sites. At BRANY because we have worked with a multitude research sites, we are able to benchmark rates across regions and types of institutions. This positions research sites for better leverage in budget negotiations with sponsors.
Budgeting for a clinical trial is essential in ensuring fair compensation for the value of services offered by a research site. However, the field is complex and there is a large margin for error that can put the institution at risk of non-compliance. It is important for institutions to leverage the expertise of analysts with a comprehensive understanding of new guidelines, as well as standards that will ensure fair compensation and adherence to federal rules.
Proposed Cures 2.0 Act May Have Implications for Researchers
Members of the U.S. House of Representatives have introduced updates to the 21st Century Cures Act, which was signed into law in December 2016. The proposed legislation coincides with a detailed concept paper the White House published Tuesday in Science Magazine outlining their vision for the new research agency.
The 21st Century Cures Act, known as “Cures”, was initiated to modernize the U.S. healthcare system. The far-reaching law included provisions to advance precision medicine, accelerate the development of new medical products, and bring new innovations to patients more efficiently.
The new bill, called the Cures 2.0 Act would create an Advanced Research Projects Agency for Health, or ARPA-H, and would authorize more than $6.5 billion to run the agency. The mission of ARPA-H will be to speed transformational innovation in health research and speed application and implementation of health breakthroughs.
Under the terms of the lawmakers’ proposal, the new ARPA-H would be largely modeled after the military’s Defense Advanced Research Projects Agency, or DARPA, which has been responsible for successfully developing some of the most significant technological advancements of our time, including the Internet, GPS and self-driving cars. DARPA initially funded mRNA vaccine technology, which led to the development of a highly effective COVID-19 vaccine in record time that’s helped slow the spread of the virus both in the U.S. and abroad.
While the 21st Century Cures Act sought to improve how new drugs and treatments are researched and developed in the U.S., Cures 2.0 seeks to improve how those new treatments and therapies are delivered to patients.
The bill provides $25 billion to independent research institutions, public laboratories and universities throughout the country to continue their work on thousands of federally-backed projects. In addition to the funding, some of the sections of the legislation will have direct implications for researchers, specifically:
- Increase diversity in clinical trials.
- Require FDA to expand the collection and use of “real world evidence” to aid in the development of new, patient-focused treatment approaches.
- Require study sponsors to collect patient experience data in clinical trials.
- Ensure coverage for clinical trials under existing standard of care: allows Medicare to cover the costs of their beneficiaries in PCORI-funded clinical trials
- Increase access to telehealth services for patients covered under Medicare, Medicaid or the Children’s Health Insurance Program (CHIP) — possibly opening opportunities for more remote clinical trials.
- Provide grants for innovative clinical trial design and patient experience data to further build the science in these areas.
- Minimize or remove requirements for IND applications to initiate accelerated approval if sponsors meet proper criteria.
- Allow for use of evidence such as clinical evidence, patient registries, or other real-world evidence, to fulfill post approval study requirements to confirm the predicted clinical benefit of a therapy.
Reps. Diana DeGette (D-Colo.) and Fred Upton (R-Mich.) plan to hold roundtables about their proposal in June and July with the aim of releasing a final bill after Congress returns from its August break, according to reports.
ARPA-H Fact Sheet (https://upton.house.gov/uploadedfiles/final_cures_2.0_2-pager.pdf)
A section-by-section summary of the bill https://degette.house.gov/sites/degette.house.gov/files/Cures%202.0_DD%20SxS_FINAL1.pdf
Article published in Science (https://science.sciencemag.org/content/early/2021/06/22/science.abj8547)
Clinical Trials: virtual, remote, or decentralized?
What does it mean to conduct a virtual clinical trial? What about remote, decentralized, hybrid, or siteless studies? These terms are sometimes used interchangeably. But there may be value in distinguishing how these models can facilitate recruiting subjects and change the way clinical trials have traditionally been conducted.
Advances in mobile and digital health technologies have allowed investigators to expand their research efforts. Fitness trackers, smart watches, and video conferencing are just a few examples of the technologies that researchers are leveraging in their trials. This can allow them to expand data collection and recruit participants beyond their immediate communities, thus expanding their reach.
When the COVID-19 pandemic caused clinical trials to pause enrolling new participants in clinical trials, the ability to introduce remote or virtual visits, benefited institutions, research participants and research sponsors. Additionally, remote or hybrid trials may free up facilities at institutions allowing space to be available for other services to be provided. Research administrators should still consider the possible increased cost in staff, as some studies may require at-home visits and other coordination.
Additionally, more research subjects may have opportunities to participate in clinical research where they may not have otherwise. Patients for whom transportation to medical centers or research facilities were a barrier might now have access to both observational and interventional trials. Some leaders suggest that these kinds of virtual trials may finally herald the promise of patient-centric trials.
Experts believe that the move toward virtual trials that occurred during COVID lockdowns may continue even as society starts to open.
Decentralized trials (DCTs) are typically not run from a traditional research site. There may be a coordinating “hub” with a principal investigator and staff, but they are not necessarily headquartered at a specific location. These studies are usually designed to screen patients and enroll them online with e-consents. Research staff can conduct study visits using home care and/or telemedicine visits.
Some refer to DCTs as “siteless” trials.
Regarding remote clinical trials, over the past year we’ve taken this to mean that some or all aspects of a traditional clinical trial operating from designated research site are being revised to allow for activities to be completed remotely outside the physician’s office (e.g. shifting visits to telemedicine visits, arranging for blood work at a lab or at home). This may result in very limited or non-existent physical contact between the investigator and the patient or subject.
Impact on Protocols
The design of a protocol for a remote or decentralized trial should address many of the critical issues of a traditional trial. These are just a few considerations:
- Technology to be used to monitor patients — smartwatches, phones, etc.
- Frequency and logistics of video or virtual visits
- Procedures for home visits
- Where and how any necessary lab or blood draws will occur
- How participants will receive devices or drugs, in the case of interventional trials
Perhaps two of the biggest concerns regarding virtual trials of any kind are data privacy and the quality of the data collected. Any transmission of data over the Internet is susceptible to hacking. Likewise, the use of third-party smartphones and tracking devices leads to questions of their security.
Without direct professionally trained staff oversight, participants are left to their own devices. They must ensure receipt of medications or devices. They must store the medication appropriately, take it according to instructions, and often self-report. They may or may not be adept at the technologies being used.
Decentralized clinical trials existed long before COVID-19. The Clinical Trials Transformation Institute issued recommendations in 2018. The pandemic did accelerate the use of virtual and hybrid trials, however. Experts believe the trend will likely continue even as society starts to open. We will continue to monitor any regulatory guidance and trends in this area.
Restarting Research Projects and Programs
The COVID-19 pandemic had significant impacts on clinical trials and research programs. According to researchers at Penn State, over 80 percent of clinical trials were suspended between March 1 and April 26, 2020, mostly due to the pandemic. The impact was more substantial for government or academic-funded studies than for sponsored trials, according to their study, which was published in March 2021. Among other concerns, researchers cited the challenges associated with recruiting and following up with patients.
Research leaders assembled task forces and started planning for the re-start of clinical and lab research as early as last summer. With unpredictable surges in cases in different states, the restart of research has not been uniform. This has required a high degree of flexibility among leaders and staff.
As vaccination programs roll out across the country, medical center campuses are updating their return-to-campus policies to accommodate the shifting landscapes. Physical distancing, use of masks and encouraging staff to continue remote meetings are still part of many campus policies. Each institution has to assess risk based on local risk factors and patient populations. Research professionals must constantly revisit processes and procedures for starting or continuing clinical trials programs, as well.
For industry sponsored studies, many trials shifted to remote monitoring and implemented telemedicine visits to minimize exposure to the coronavirus. Most institutions prohibited sponsor representatives from conducting in person site initiation visits and clinical trial monitoring. These restrictions are also beginning to be lifted.
Evaluate and Re-Allocate Resources
Campus closures were disruptive for staff as they often shifted their focus to supporting COVID activities on medical campuses. Some staff may return, others not. Turnover among clinical research coordinators was already high before the pandemic, and uncertainty about the future may have exacerbated this.
Recruiting and training new clinical research coordinators can be time-consuming and challenging under current circumstances. Research teams may need flexible staffing, or to ramp up activities quickly with limited staff. In these cases, it may be prudent to consider outsourcing much of the administrative and compliance work associated with clinical research.
Managing the many aspects of the COVID-19 pandemic this past year has also depleted financial resources at many institutions. Institutions have implemented hiring freezes because funding is scarce. Budgets for 2021/2022 are being cut all around including areas such as research administration.
Another question to consider: as restrictions are lifted to allow more clinical trials to begin again, and to open organizations for in person monitoring and site initiation visits will staff be available to support these initiatives?
Review Protocols for Deviations and Violations
It is important to understand the difference between a protocol deviation versus a violation, as there are implications for reporting requirements and IRB review.
Generally speaking, a protocol deviation occurs when, without significant consequences, the activities on a study diverge from the Institutional Review Board-approved protocol. For example, a patient may have missied a visit window because s/he is traveling.
A protocol violation is more serious. It refers to a divergence from the protocol that materially:
- reduces the quality or completeness of the data
- makes the Informed Consent Form inaccurate, or
- impacts a subject’s safety, rights, or welfare
If there are changes to the protocol, then IRBs may need to review updated patient consent forms. Additionally, some institutions are implementing e-consents and other technologies.
Communication with participates goes beyond consents. As return-to-campus protocols are modified, staff must advise research participants of any changes. For example, if a study moved to telehealth visits, and is now re-opening to in person visits, participants should receive the campus COVID guidelines prior to their next visit. Coordinators may need to communicate with participants regarding options that were implemented in response to COVID-19, and whether they will still be options as in person visits resume.
Identify Potential Budget Implications
Changes in protocols, methods of obtaining consents or conducting follow-up visits are just three ways in which a study budget can be impacted. Every change or accommodation to updated policies and procedures should be checked against the budget to ensure accuracy and appropriate reimbursement.
Experts are still debating what the future of work — and therefore, the future of clinical research — may look like post-pandemic. Regardless of the short- and long-term implications, it is essential for research staff to remain diligent and flexible in overseeing and updating procedures and policies.
A Methodological Approach to Coverage Analysis
To ensure appropriate reimbursement for the services provided to a patient in a clinical trial, research sites must develop a budget for each study. One important step in developing a clinical trial budget is conducting a “coverage analysis,” also known as Medicare Coverage Analysis, sometimes referred to an MCA.
An MCA identifies the services for which U.S. Centers for Medicare & Medicaid Services (CMS) will pay under the Medicare Clinical Trial Policy also known as NCD 310.1. A methodical analysis ensures that a research site receives appropriate and correct reimbursement for services. It also helps avoid compliance pitfalls with regard to inappropriate billing.
The Risk of Non-Compliant Billing
Providers are not permitted to bill Medicare for medical care and services for which the clinical trial sponsor has agreed to pay.
Failure to comply can result in severe penalties, as well as civil and criminal actions. There have been some high visibility cases in which health systems and academic medical centers have settled allegations of violation of the False Claims Act. Some settlements have resulted in payment in the millions of dollars to the U.S. government.
A Methodical Approach
Determining the eligibility of a clinical study’s related tests, procedures or interventions for Medicare coverage requires a detailed review of the clinical events specified in the protocol to determine which can be reimbursed. This sometimes cumbersome and time-consuming process is essential.
The first step is to determine whether the trial qualifies for coverage. To qualify, a trial should meet these criteria:
- The purpose of the trial must be to evaluate an item or service that falls within a Medicare benefit category. For example, physicians’ services, durable medical equipment and diagnostic tests would be covered; cosmetic surgery and hearing aids would not.
- The trial must have a therapeutic intent. Does it potentially improve the participants’ health outcomes? In other words, it cannot be a study designed exclusively to test toxicity or disease pathophysiology.
- The trial will enroll patients with a diagnosed disease rather than healthy volunteers.
These three requirements are insufficient by themselves to qualify a clinical trial for Medicare coverage of routine costs. Clinical trials also should have the following desirable characteristics. Here is where institutions must work closely with their investigators, as well as the study sponsors, to ensure documentation in answer to these questions:
- Is the principal purpose of the trial to test whether the intervention potentially improves the participants’ health outcomes?
- Is the trial supported by available scientific and medical information or is it intended to clarify or establish the health outcomes of interventions already in common clinical use?
- Does the trial duplicate any existing studies?
- Is the trial design appropriate to answer the research question being asked in the trial?
- Is the trial sponsored by a credible organization or individual that is capable of executing the proposed trial successfully?
- Does the trial comply with federal regulations relating to the protection of human subjects?
- Are all aspects of the trial being conducted according to the appropriate standards of scientific integrity?
Some trials are deemed to have these desirable characteristics and automatically qualify. The following are examples of trials that would automatically qualify:
- Trials funded by a federal agency, such as the National Institutes of Health, the Centers for Disease Control and Prevention or the U.S. Department of Veterans Affairs, among others.
- Trials supported by a center or cooperative group that is funded by a federal agency.
- Trials conducted under an investigational new drug application reviewed by the Food and Drug Administration.
- Drug trials that are IND-exempt (see the Medicare Coverage Clinical Trials Final National Coverage Decision for Routine Cost in Clinical Trials for more details)
National vs. Local Coverage Determination
Analysis becomes even more complicated when considering Local Coverage Determination, the policies written by local or regional fiscal intermediaries representing CMS. This is where many of the pitfalls occur and where many institutions get lost, and also where state Medicare contractors make the majority of coverage decisions. A procedure or test may be covered in New York, but not California.
How device trials differ
In 2015, CMS and regulatory agencies streamlined the process of assessing coverage for IDE device trials. Sponsors, or device manufacturers, must submit trials to CMS for review and approval at the national level. Prior to this change, sponsors and sites had to wait until IRB approvals were obtained and submit documents to the local Medicare contractor. This CMS approval process applies to category A and B trials, as considered by the FDA:
- Category A devices are experimental, “…a device for which ‘absolute risk’ of the device types has not been established (that is, initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.” In other words, they are novel, which there is not enough information about the devices to make them eligible for reimbursement for the device itself.
- Category B devices are non-experimental, or investigational, meaning “…a device for which the incremental risk is the primary risk in question (that is, initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.” These are similar to devices already in the marketplace, and the study is evaluating a modification
That said, institutions must still conduct the coverage analysis to determine what is clinical care vs. research.
Standardizing and streamlining the process
Establishing an algorithm of questions and a process to collect the appropriate documentation is essential. It is also important that institutions conduct this analysis as efficiently and expeditiously as possible to minimize the risk of study initiation delays.
These are some of our recommendations for best practices.
Centralizing the process of collecting and archiving all the relevant components, such as protocol, consent, sponsor budgets, contracts, FDA letters, etc., can ensure a degree of consistency in the review process. Some institutions are considering centralized MCAs, similar to central institutional review boards, which have been demonstrated to accelerate the start of studies at many institutions.
Establish a standard operating process that defines the procedure from the time a provider sees a patient when the service is provided, to how the service is documented and communicated to the payers. This should include how institutional electronic health records and clinical trial databases should communicate with each other.
Provide ongoing education to research personnel. Experience and knowledge vary widely from one institution to another, and there is a shortage of well-trained analysts with this expertise. Additionally, research and billing staff should understand regional and state differences in coverage.
Work with the investigator to review the informed consent carefully to clarify costs, FDA status, visits and procedures; you should also review the entire protocol, not only the schedule of events. Additionally, work closely with the study sponsor — the pharmaceutical or device company — to differentiate between routine care and care provided by the sponsor.
Alex Morillo is the program director for Coverage Analysis at the Biomedical Research Alliance of New York (BRANY—www.brany.com). He works with research institutions across the country to ensure projects meet the requirements for Medicare reimbursement. He also provides assistance to research sites in Medicare billing compliance self-audits. Before joining BRANY, he worked in the clinical trials office for New York University, where he managed a portfolio of over 200 clinical trials.
Pandemic-related Mental Health Care Needs Continue to Increase, Highlighting the Need for More Social-Behavioral Research
A report published last week by the Centers for Disease Control & Prevention (CDC) shows an increase in anxiety, depression and people’s need for mental health services. According to the survey, between August 2020 and February 2021, the percentage of adults with recent symptoms of an anxiety or a depressive disorder increased from 36.4 percent to 41.5 percent. The percentage of those reporting an unmet mental health care need increased from 9.2 percent to 11.7 percent. Increases were largest among adults aged 18–29 years and those with less than a high school education.
Last year, the National Institutes of Health (NIH) convened a consortium of federal agencies to encourage research in social, behavioral and economic impacts of COVID-19, particularly for vulnerable populations. The agencies directed funds to jumpstart research efforts.
The research that has evolved over the last year examines a variety of topics, including:
- The large-scale behavior changes and significant psychological burdens on individuals
- How people navigate threats, as well as social and cultural influences on behavior
- How communities support individuals in managing stress and coping
- The role of social isolation and relationships
- Health education and risk communication
The Need for IRBs with Specific Expertise in Social-Behavioral-Educational Research
Social behavioral research applies the behavioral and social sciences to the study of people’s responses to certain stimuli (both external and internal). Such research is conducted in academic disciplines such as:
- political science
Social, behavioral, and educational research (SBER) has its own set of unique needs. An IRB review of these protocols necessitates expertise that is different from IRBs evaluating biomedical research protocols. These IRBs are comprised of experts who are well versed at identifying and evaluating the psychological and social risks that are often associated with SBER. These experts — often nurses, psychologists, epidemiologists, and educators — evaluate risks such as:
- Questionnaires about illegal behaviors that may damage subjects’ reputations or raise legal concerns
- Collecting information from subjects about activities that may place them at risk of harm or legal action
- Compromising a subject’s confidentiality, possibly jeopardizing employment and/or insurance coverage
- Research involving deception
- Providing subjects with unwelcome and disturbing information about themselves
- Research that involves use of questions and/or procedures that can cause stress or embarrassment
Research will include observation, interviews, surveys, and data analysis. Some ongoing school-based research is also likely.
Most social behavioral research involves no therapeutic intervention, but the potential risks of social or psychological harm must still be considered. BRANY’s SBER IRB is specifically dedicated to the review of these important protocols, both retrospective and prospective, with particular focus on minimizing risk and protecting human subjects.
 Vahratian A, Blumberg SJ, Terlizzi EP, Schiller JS. Symptoms of Anxiety or Depressive Disorder and Use of Mental Health Care Among Adults During the COVID-19 Pandemic — United States, August 2020–February 2021. MMWR Morb Mortal Wkly Rep. ePub: 26 March 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7013e2
What is the DSMB and Why You Should Know
The Data and Safety Monitoring Board (DSMB) established to monitor COVID-19 vaccines this week announced they were reviewing the clinical trial data submitted by Astra Zeneca for their COVID-19 vaccine. But what is a DSMB, and why is it important for clinical research sites to know?
A Data and Safety Monitoring Board (DSMB) is an independent group of experts that objectively evaluates trial data periodically for integrity and to assure the safety of clinical trial participants. DSMBs must provide the recommendations from their evaluation to researchers such as those at the National Institutes of Health (NIH) or for industry trials the sponsor (e.g. pharma or device companies). Individual institutes within the NIH have their own policies regarding data and safety monitoring plans and data and safety monitoring boards.
The panel of scientists is independent of both the manufacturers developing a drug or vaccine, as well as the government officials who will approve it.
The NIH requires the establishment of data safety monitoring boards for multi-site clinical trials involving interventions that entail potential risks to participants (generally Phase III clinical trials).
The primary responsibilities of the DSMB are to:
- periodically review and evaluate the accumulated trial data for participant safety, trial conduct and progress, and, when appropriate, efficacy, and
- make recommendations concerning the continuation, modification, or termination of the trial
DSMBs have received more public recognition among the general media because of their role in ensuring the safety of the many current COVID vaccine trials. Both AstraZeneca and Johnson & Johnson, two companies working on COVID-19 vaccines, paused clinical trials on the advice of their DSMBs when two patients, one enrolled in each trial, experienced adverse events. After a review of the data, the DSMBs determined that both trials could continue safely. Although the FDA is not required to take the advice of the DSMB, they often do.
It is very important that DSMBs operate independently to maintain objectivity and make unbiased decisions when interpreting data. In some cases, particularly in non-NIH-funded trials, drug developers might establish their own independent committees.
Why this matters to clinical research sites
For NIH-funded studies, regulatory policy has explicitly identified required communications that must occur between DSMBs and Institutional Review Boards (IRBs). The two groups have distinct and complementary roles in ensuring the safety of human subjects in clinical trials.
A DSMB reviews, among other things, the following:
- Data quality, completeness and timeliness
- Site adherence to the protocol
- Performance of individual centers
- Adequacy of compliance with goals for recruitment and retention, including those related to the participation of women and minorities
The DSMB then provides feedback at regular and defined intervals to researchers and/or the IRBs.
This continuous feedback loop is designed to ensure the safe execution of a clinical trial, and requires close cooperation among the researchers, the sponsoring organization and the DSMB.
Read the official statement from NIAID regarding the AstraZeneca data:
Guide to Remote Audits
The United States reached the one-year anniversary of the first confirmed case of COVID-19, on January 15. Even now, as the rollout of vaccinations is underway, institutions are still facing campus and facility closures. We cannot underestimate the impact of COVID-19 on clinical trials and the research community. Institutions have had to refocus resources toward pandemic-related clinical care and research, which has caused delays, disruptions and cancelations of research in other clinical areas. Research coordinators and support staff continue to work remotely or in hybrid work situations.
Despite this, research professionals have demonstrated remarkable resilience and flexibility in adjusting to the new landscape. Over the last year, institutions have leveraged technologies to continue or start up clinical trials. Telemedicine has increased opportunities for remote consent and virtual study visits.
Restrictions on travel, in-person visits and access to research offices forced federal regulators to scale back their in-person surveillance activities, while increasing their remote audits to gauge compliance with Good Clinical Practices (GCP), Good Manufacturing Practices (GMP), and human subject protection (HSP). Investigators must be prepared for announced or unannounced inspections, particularly remote reviews.
A variety of situations can trigger an FDA inspection, from a serious adverse event (SAE) to reported violations of protocols. Just as your research team should be well prepared for in-person inspections, so should you be prepared for a remote visit. These are some of the areas where your team can prepare. In some instances, your team should coordinate with the IT department to ensure a secure, yet easily accessible, repository of information.
Gather and centralize stakeholder contact information
The names and contact information (mobile phones, pagers and email) of all key staff should be in a central place, such as a spreadsheet. This record can include:
- principal investigator (your materials should include the PI’s CV)
- clinical research coordinators
- laboratory technicians
You should also include any staff who should be notified in case of an audit, including contacts in:
- medical records
- risk management
Your contact list should include your primary contact at the study sponsor and/or CRO.
Digitize study documents
Depending on the requirements of your institution or the study sponsor, you may want to consider scanning regulatory documents and keeping them in a secure cloud-based file system. Consider including these items:
- IRB documentation, including the approval letter and amendments
- consent form (at least the latest version)
- study reference manual
- study protocol(s)
- sponsor instruction manuals
- policies and procedures
- roles and responsibilities for each of the key team members
- correspondence with the sponsor
- certifications (for example, for the laboratory)
- other essential documents as per Good Clinical Practice (GCP)
You should be prepared to upload participant documents such as signed Informed Consent Forms, Case Report Forms, and source documents to a file sharing application, following institutional requirements of redacting protected health information, if applicable. You may want to explore with IT granting auditors remote read-only access to the Electronic Medical Record for the participants selected for the remote audit.
Prepare a plan with stakeholders
The nature of remote audits may require more time to prepare requested documentation. It is important to prepare a plan and to educate your internal stakeholders on the procedures and areas of responsibilities in the event of an audit. A mock audit can test everyone’s response and identify risks and gaps. Don’t forget to include the IT department and staff in other departments who may need to play a role.
In the case of paper documents that are not scanned and uploaded in advance, you should have a plan for doing so upon request of the auditors. Identify a secure and HIPAA compliant storage platform and the mechanism by which you can obtain and upload those documents remotely that adheres to the institutional policy.
Be prepared to deliver a virtual “live” walk-through of facilities. Identify who will provide the tour and the technology necessary to do. Ensuring strong Internet connectivity in those areas, such as basement laboratories and other potential weak Wi-Fi zones can ensure a smoother experience for everyone.
It’s likely that remote work and, therefore, remote research surveillance will be part of the workflow for some time. Preparing for a remote audit can decrease stress and ensure clear communication among all the stakeholders.
Best Practices for Remote IRB Meetings
The campus closures necessitated by the pandemic in 2020 forced many research administration officials to adopt virtual meetings to continue their work. People scrambled to set up their home offices, to secure Wi-Fi networks and create accounts on videoconferencing services. The Internet offered dozens of articles on how to improve online meetings to encourage engagement and collaboration.
Now, nearly a year later, organizations and companies continue to struggle to run efficient and effective virtual meetings. Online meetings have challenges that many of us have experienced. It’s difficult to read body language or have eye contact. Some technologies have lag times that cause people to talk over each other. Virtual meeting attendees are more prone to interruptions and distractions.
The pandemic forced a dramatic and rapid switch to virtual meetings for Institutional Review Boards, as well. Over half of attendees at a webinar hosted by CITI Program in February 2020 indicated that they held IRB meetings exclusively in person, with about another 40 percent conducting hybrid meetings. Only six percent indicated virtual-only meetings.
BRANY’s IRB has been meeting virtually for several years. These are some of the best practices we have learned, as well as highlights from the CITI webinar mentioned earlier. A recording of the webinar is available on the CITI Web site.
Beyond the usual accommodations required of virtual meetings, Institutional Review Boards have specific regulatory requirements regardless of whether they meet in person or virtually. Ensure that your meetings comply with the regulatory components of 45 CFR 46.111 and 21 CFR 56.111.
Leverage Supporting Technologies
Virtual meetings can be supported with technology-driven solutions specific for managing IRBs. IRB management systems can be very robust and help streamline the IRB review process by enabling online submissions, sending electronic alerts, and storing key documentation, such as IRB policies and determination letters. Additionally, these tools are extremely useful for generating meeting agendas, meeting minutes and can be utilized during IRB meetings to share relevant documents with the entire IRB committee via video conferences.
Having a predictable and consistent agenda and process can help keep the meeting running smoothly and on time. Your IRB may want to consider implementing standard meeting procedures, such as those found in Robert’s Rules of Order, with the specific steps for reviewing protocols. It may be useful to distribute these review guidelines to the IRB members as well as the investigators.
Likewise, meetings should be regularly scheduled and on members’ calendars. Standing meeting days and times can increase the likelihood of convening a quorum, one of the regulatory requirements of IRBs.
Training members on the remote meeting platform will help the meeting to run smoothly and reduce the amount of disruption that can occur when people are not proficient at the audio and video technology. The following areas are particularly important:
- Signing in properly especially when using both a computer and phone. If audio is active on both devices it will create an echo, which is extremely distracting to all participants
- Using the mute function when others are speaking
- Remembering to unmute
- Slow internet speed can cause delays in audio transmission
Agree on Specific Roles
Running a successful IRB meeting requires several people, and their roles should be clearly defined in advance. An IRB coordinator or meeting specialist, for example, can send calendar reminders, links to the necessary materials, and instructions for dialing in to the meeting. Another critical role in an IRB meeting is that of the scribe, or minute-taker. Accurately capturing the vote count for items reviewed by the committee is also a key responsibility. Completing a roll call to verbally verify voting may also be a task assumed by this role.
Set Expectations for Behaviors and Procedures
In addition to having clearly defined roles, it is important that the committee understand and consent to certain expected behaviors. For example, it is important to agree on these questions:
- Does the committee require that cameras be turned on for video calls?
- How will the chair acknowledge speakers to ensure each individual has an opportunity to share thoughts?
- How will notes be taken and shared?
- When will deliberations be considered complete and voting can commence?
Advise meeting participants in advance if you are recording the meeting.
Practice Active Listening
Because the usual dynamic of in-person meetings is not realistic with virtual meetings, it is important to use active listening skills to ensure that people are not only heard, but also understood. Aside from paying attention and withholding judgment, participants — led by the example of the chair — can use skills such as reflecting, clarifying and summarizing. This also helps improve accuracy for notetaking.
While many people are anxious to get back to their offices and resume in-person meetings, the reality of virtual meetings — at least some of the time — is likely to remain a bit longer. Even beyond the pandemic, IRBs should be prepared to respond to possible future emergency situations that necessitate virtual meetings. These and other best practices can make virtual IRB meetings not only smooth, but compliant with regulations.
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.
Is Your Institution Prepared to Identify Exempt Research?
The disruption of clinical research as a result of COVID-19 cannot be overstated. Virtually everything about developing protocols and starting clinical trials has been upturned. In some cases, trials have been closed indefinitely. Others have been delayed or streamlined. Much of the interaction, such as IRB review meetings, has been shifted online, decentralized or outsourced to free up resources in the fight against the pandemic.
Anecdotally, we have observed a change in the types of protocols submitted for IRB review, as many investigator-initiated trials have pivoted toward better understanding of COVID-19. At BRANY, we have seen an influx of exempt research — protocols that pose minimal risk and fit into pre-specified categories that are exempt from IRB review. This type of research still requires a determination that it meets criteria for exemption. The regulations do not specify who at an institution may determine that research is exempt under 45 CFR 46.101(b). However, the U.S. Office for Human Research Protection (OHRP) recommends that, because of the potential for conflict of interest, investigators not be given the authority to make an independent determination that human subjects research is exempt. The IRB is often tasked with making exempt determinations.
Institutions should develop standards and procedures for determining research is exempt. However, this can be complex and complicated as exempt categories must be interpreted for specific situations. In developing these policies, OHRP recommends the following:
• Develop standardized mechanisms for collecting sufficient information to make the determination. This can include checklists, standard operating procedures and requirements for training.
• Policies should clearly define who has authority to make these determinations and provide sufficient training for those people.
• Define categories for exemption and use them in making the determination. This is useful in case of audit, but also helps the institution to establish policies.
• Provide clear guidance to investigators about federal and institutional guidelines.
This last point is crucial, as there is no federal mandate that anyone other than investigator make the determination that a research study is exempt. Some institutions may be tempted to expedite research and avoid delays by allowing investigators to make these determinations. The provision of detailed checklists, or the use of a guided protocol writing tool such as ProtocolBuilder, may help the investigator in these cases. The OHRP, and we at BRANY, strongly advise that someone other than the investigator make this determination in order to avoid possible conflict of interest.
Research institutions and academic medical centers must continue to adjust to the rapidly shifting landscape brought on by COVID-19. Resources have focused on understanding the pandemic and have been funneled toward both interventional and observational research in this area. This has resulted in a possible increase in investigator-initiated studies that may be considered exempt. Institutions may need to review their policies and procedures for making these determinations to ensure they are both in compliance and, more importantly, continue to protect human subjects.
Trends: What We Are Watching in 2021
We know we are not alone when we say we are happy to put 2020 behind us. It was a challenging year for everyone, and we look forward to better days ahead. Despite the difficulties that the research community faced, we witnessed remarkable flexibility, resilience and creativity in dealing with significant hurdles. Last year lent new meaning to the phrase “hindsight is 2020.” In this article, we look ahead at 2021 and share the issues that we will be monitoring.
Diversity and inclusion in clinical trials
The COVID-19 pandemic highlighted serious racial and economic disparities in health care. Some racial and ethnic minority groups have been disproportionately affected by COVID-19. Conditions in the places where people live, learn, work, play, and worship affect a wide range of health risks and outcomes, such as COVID-19 infection, severe illness, and death. Long-standing inequities in social determinants of health that affect these groups, such as poverty and healthcare access, are interrelated and influence a wide range of health and quality-of-life risks and outcomes.
Likewise, racial and ethnic minorities are underrepresented in clinical trials. The research community, which includes industry sponsors and government agencies, is actively pursuing strategies that address disparities in clinical research. The FDA issued guidance in November aimed at enhancing diversity and encouraging inclusivity in medical research, specifically in the development of medical products. The industry trade group PhRMA adopted Principle 6, Commitment to Enhancing Diversity in Clinical Trial Participation, aimed at enhancing racial and ethnic diversity among clinical trial participants, with an effective date of April 14, 2021.
We will be watching how industry-sponsored and investigator-initiated trials implement strategies for increased inclusion.
Re-starting Clinical Trials
The pandemic led to the halting of hundreds of clinical trials. Lockdowns and other mandatory public health orders forced research staff to work from home and made in-person patient visits nearly impossible. Additionally, staff resources were redeployed to shore up shortages and support hospitals’ responses to the surge in COVID-19 cases in communities in the U.S. and around the world.
For some patients, particularly with end stage disease, the suspension of clinical trials had serious implications. Likewise, enrollment for new trials staggered as patients were wary of visiting any medical facilities. In an editorial in JAMA, researchers said “Mitigation efforts [against COVID-19] interfere with all aspects of a successful clinical trial: efficient accrual and randomization, intervention adherence and delivery, and outcome collection.”
Even now, research institutions are grappling with solutions to reduce the impact of fluctuating and shifting public health mandates on existing trials. Investigators continue to evaluate how to re-start trials safely.
Increase in Observational Trials
Investigators have immense opportunities to design and implement investigational trials evaluating patient outcomes and long-term effects of COVID, as well as different treatment modalities. Additionally, researchers may consider trials evaluating various aspects of the different COVID vaccines currently on the market as well as other that are in the development and approval pipeline.
Opportunities for social-behavioral-education research
Stay-at-home orders and increased isolation, negative impacts on the economy and lost jobs, not to mention a daily barrage of dramatic news and social media coverage, have led to an increase in stress and anxiety. The pandemic also led to a disruption in mental health services.
We are still learning what the long term social and behavioral impacts will be. But we expect to see an increase in studies to evaluate this.
Remote Monitoring and Decentralized Clinical Trials
Since the pandemic began, over half of all active clinical trials are using remote and virtual support, according to a study by The Tufts Center for the Study of Drug Development. We expect to see the continued use of telemedicine, remote monitoring and virtual IRB meetings and reviews.
Research professionals will continue to make adjustments to how they run research programs. Many institutions may need to make policy decisions in the absence of specific regulatory guidance.
In September 2018, the Clinical Trials Transformation Initiative https://www.ctti-clinicaltrials.org/projects/decentralized-clinical-trials defined decentralized clinical trials (DCTs) as those executed through telemedicine and mobile/local healthcare providers (HCPs), using procedures that vary from the traditional clinical trial model. For example, the investigational medical product is shipped directly to the trial participant).
The research community may need to continue to develop awareness and understanding about DCTs and/or hybrid trial designs, and what is in the best interest of patient safety as well as research integrity.
Using Digital Technology and Telemedicine in Clinical Trials
The trend toward digital technology, such as health tracking devices and virtual clinic visits, had started before COVID. The pandemic accelerated the implementation of these technologies to allow study participants to sign consents, submit vital statistics and data, and communicate with clinical research coordinators and investigators — all from the convenience of their home.
We are loath to make any predictions in this most unpredictable time. The story of COVID and its impact on research is still unfolding. With that, we plan to continue monitoring these issues and offering support to clients that are navigating these uncharted circumstances.
Happy new year from the team at BRANY.
Increasing Diversity in Clinical Trials
The FDA issued guidance in November aimed at enhancing diversity and encouraging inclusivity in medical research, specifically in the development of medical products. FDA Commissioner Stephan M. Hahn, M.D., wrote that “in order to promote public health, it is important that people who are in clinical trials represent the populations likely to use the potential medical product.”
Last week, the industry trade group PhRMA issued voluntary guidelines to members aimed at enhancing racial and ethnic diversity among clinical trial participants. Those guidelines go into effect in April 2021.
The FDA guidance discusses:
- broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials;
- developing eligibility criteria and improving trial recruitment so that the participants enrolled in trials will better reflect the population most likely to use the drug, if the drug is approved, while maintaining safety and effectiveness standards; and
- applying the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.
The final FDA guidance addresses demographic diversity as well as non-demographic diversity, including people with co-morbidities, disabilities and wider weight ranges. Broadening inclusion eligibility for clinical trials impacts protocol design and methodological approaches.
The PhRMA guidelines specifically focus on outreach to communities of color to reduce health disparities. Activities include outreach and education, as well as the reduction of barriers to participation.
Exclusion and eligibility criteria necessarily balances risk of adverse events against the potential benefit of the research. Pregnant women, people with chronic or severe kidney disease, or complex medical conditions are often excluded from clinical trials due to risk. However, the FDA cautions against excluding certain populations out of habit or template, rather than based on strong clinical or scientific justification. Both sets of guidelines encourage broadening eligibility criteria to increase diversity when scientifically and clinically appropriate.
The FDA guidance addresses the logistics of participation and offers strategies for minimizing the burden on enrollees. For example, certain populations may find it difficult to visit research sites frequently. Researchers and sponsors are encouraged to consider alternative methods of engaging with participants, including phone or virtual visits, email, social media and digital devices.
Investigators and sponsors are encouraged to adopt enrollment and retention practices that enhance inclusiveness. Engaging patient advocacy groups in the design of protocols; increasing outreach and education through community organizations; expanding research sites to ethnic or underserved neighborhoods; hosting frequent recruitment events; and developing recruitment materials in multiple languages are just some of the suggestions.
While both the FDA and PhRMA address sponsored clinical trials, it can also influence investigator-initiated trials.
Broadening eligibility criteria and adopting more-inclusive enrollment practices should improve the quality of studies by ensuring that the study population is more representative of the population that will use the medical product if it is approved.
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.
How COVID-19 Has Impact Clinical Trial Budgeting
As COVID-19 swept across the United States earlier this year, many research centers found themselves pausing or stopping clinical trials and shifting their work from an office or clinic to their homes. Clinical research staff pivoted their focus to support the COVID-19 response, or to launch critical studies focusing on COVID-19.
As some research staff return to campus, research sites are reviewing their study budgets and making important adjustments. We have outlined some of the key areas that may have clinical trial budget impacts.
Without the ability to visit campuses in person, sponsors must conduct monitoring visits virtually and remotely. It may seem like this is less time consuming and convenient. In fact, it may take more time and coordination to prepare medical records to review remotely from the research site perspective.
Study coordinators must collaborate with their institution’s IT teams to develop HIPAA-compliant remote access for sponsor or CRO study monitors. Within each institution, there may be many security steps that must be achieved prior to granting access to external parties. It can even be more complicated when there is a lot of staff turnover; monitors can change frequently during the research study lifecycle. In some cases, research staff might not have the proper equipment at home to access and/or transmit records. Research staff may have to print or scan medical records, then redact them and send them securely to the monitor.
Research sites should have their staff carefully track time spent on the extra steps and be sure to account for added time and effort in their budgets. Under pre-COVID circumstances, sponsors often provided arguments for not covering monitoring visits as it was considered a part of doing business. However, in the case of remote monitoring, coordinators and/or analysts should have a conversation about including the extra staff time and effort in the budget. This should include the time and effort of the IT department.
Telemedicine and Its Limits
For the sake of patient safety and whenever possible, office visits have shifted to virtual visits over the phone or videoconferencing. For patients in clinical trials, it could include engaging with the attending investigator, or a consultation with a nurse or coordinator. It is important to keep track of who participated in the virtual visit and to consider negotiating virtual visits as an item to be invoiced to the sponsor if the visit is not already covered as part of the sponsor’s budget. Keep in mind the time and effort of IT, or cost of HIPAA-compliant telecommunications technology to establish secure communication pathways among the patient, the investigator and research staff, for the purpose of the research study. If you are using online meeting platforms, such as Zoom or Microsoft Teams, there are costs associated with these applications as well.
In some cases, the protocol may call for a specific procedure such as IV drug administration. In this case, a visiting nurse or a contracted home health service may have to visit the patient’s home. The need for such a service should be identified and the logistics should be discussed with the sponsor. Budgets should include these visits as well as any costs for contracting and coordinating home health services.
COVID-19 Safety Measures
In some institutions, on-site staff are undergoing frequent COVID testing, sometimes twice a week. They also have had to stock up on personal protective equipment (PPE). As sites return to meeting study participants in person the use of PPE may increase. Consider including costs for some PPE supplies in your study budget when in person visits are required.
Many research coordinators shifted their focus to COVID-19-related projects. Many of them are now turning their attention back to research that had been put on hold, or on emerging new research projects.
Institutions have a mix of staff working at home and working in clinical environments. Administrators are encouraging more virtual meetings and contactless interfaces. This leads to a higher reliance on IT’s involvement in research to provide secure networks and communication. This, also, may mean a higher level of coordination with pharmacies, radiologists, and other clinical staff.
The return to campus and the restart of many trials requires a close look at budget to evaluate if there are any anticipated COVID-19 impacts, even if the study is not specific to the pandemic.
Investigators Face Challenges in Writing Research Protocols in the Age of Remote Working
While some research institutions are slowly re-opening their campuses, many investigators and their staff are still working remotely from home, at least part time. This has had a significant impact on both industry sponsored and investigator initiated clinical trials. Learn how to continue protocol writing even when working remotely. https://bit.ly/2QoW1NW
Telehealth, Clinical Research and Informed Consent
By most any measure, one of the biggest impacts that COVID-19 has had on the practice of medicine is the shift toward more telemedicine visits. Although the practice of delivering health services over the phone or the Internet has been around for some time, it wasn’t until the pandemic forced communities to close that clinical practices started to explore the use of technologies to continue monitoring patients remotely.
The global health crisis has forced both health care providers and regulatory agencies to pivot toward digital health services. Clinical research is no exception. Many clinical research studies were put on hold in the early days and weeks of the pandemic in the United States. Researchers and their staff were deployed to support COVID-19 efforts. Regulatory agencies had to adapt guidelines for HIPAA and other issues for the new environment. Health insurers developed policies for telemedicine and reimbursement.
Although clinical research in COVID-19 still seems to dominate at research institutions, protocols not related to COVID-19 are starting to return. Studies that were paused are also being resumed, albeit slowly and cautiously. Each institution has to assess risk based on local risk factors and patient populations. For studies that are primarily computational, or do not require in-person interventions, telemedicine may continue to dominate.
For research professionals, one critical issue is the process for consenting, or re-consenting, patients. For studies that were paused, investigators may need to re-consent patients due to necessary changes in the protocol. Participants may have to confirm their willingness to continue their participation in a trial.
These and other issues require consideration of the process of obtaining consent. Research coordinators, while familiar with the protocols, may need to adapt to the method of consent and how they explain the studies to patients via these technologies. The 2018 regulatory changes to consent forms that require a concise summary may be helpful in helping to communicate with potential participants. The remote consenting process may require more dialogue with the patient to ensure understanding.
These new processes can be an adjustment for research coordinators or others obtaining consent. Proper training on process is critical to ensure informed consents are conducted appropriately and continue to protect human subjects.
CITI Program, a division of BRANY, is hosting a webinar on informed consent on September 30, 2020 at 2PM EST.
Lessons Learned (so far) in COVID-19
Even as communities start the process of evaluating re-opening, many experts believe that a new normal will be with us for a long time. Physical distancing, face masks and ubiquitous alcohol gel will be part of daily life. The risk of recurrence spikes also looms ahead and threatens a return to stricter “stay at home” orders. Health care and higher education institutions continue to evaluate risks and will likely continue to encourage employees, including IRB and research administration staff, to work from home in order to maintain physical distancing. Research office staff have made incredibly quick adjustments in real time as the pandemic made its way through the United States.
In assisting our partners and clients make rapid changes, we learned some lessons we believe will help research institutions be more resilient in the months and even years to come.
Prepare for the unexpected
Disaster planning and business continuity are required for organizations receiving National Institutes of Health (NIH) funding. But even non-NIH funded research institutions should have robust business continuity plans in place. The elements of a disaster plan include issues such as data security and protecting human subjects.
Many organizations scrambled to get their staff up and running from impromptu home offices. From installing and learning video conference platforms to having documentation securely available online, many research professionals quickly adapted to new ways of working and collaborating despite the learning curve.
Research institutions and investigators should consider building in these technologies as a part of their daily operations:
- Web-based collaborative protocol-writing tools
- Electronic Research Protocol Management Systems and Clinical Trial Management Systems
- Online training for research staff, particularly for operations and regulatory compliance
- Secure online meeting/video conferencing applications
- Secure cloud-based document storage for regulatory materials and other essential documents
Build in flexibility
Many research institutions pivoted their resources toward COVID-19 research efforts. This means that internal resources are unavailable for ongoing work or pending projects. Being able to shift that work to external resources, including IRBs, allows for flexibility to respond quickly as situations evolve.
External IRB partners should offer processes and procedures for running IRB meetings virtually in compliance with regulatory requirements. They should also hold frequent meetings, with the ability to hold ad-hoc meetings as needed.
Other functions can be outsourced to strategic partners, particularly when rapid turnarounds are required. These include the development and management of study budgets, coverage analysis, and clinical trial agreement support.
Select the right partners
The historic scope of impact on the research community at every level demonstrates weaknesses in every system, including partnerships. As with any disaster, communication is often the first thing to fail. Tightly synchronized communication with responsive partners who act as an extension of the research team can be the difference between an inconvenience and a very costly mistake.
Research institutions have demonstrated great resilience in their response to COVID-19, and have continued to focus on human subject protection throughout their efforts. There is talk of a “new normal” in the aftermath of the pandemic. These lessons learned can help institutions retain the integrity of their research while remaining responsive to what may be a long-standing landscape in the months or years to come.
Chart Review Studies During and After a Pandemic
The current global pandemic combined with electronic medical records and data visualization technologies have resulted in unprecedented advances in real-time tracking of SARS-CoV-2, the virus that causes COVID-19, across countries, states and local communities. As the situation evolves, there will be ample opportunity and increased need for both retrospective and prospective COVID-19 research studies that involve the review of medical records.
The rapidly evolving situation in this global pandemic requires investigators to design and write protocols quickly for IRB review. A guided protocol-writing experience, as with ProtocolBuilder, streamlines the process, ensures regulatory and institutional compliance, and facilitates collaboration among researchers.
In medical record review studies, also called a “chart reviews,” a researcher may collect and analyze information that was originally collected for a different purpose, also referred to as a secondary use of data. It often involves the collection of data from medical records in order to evaluate possible relationships between different variables and specific outcomes measures. An investigator may assess biomedical, treatment or demographic variables by reviewing various elements of a medical record. These may include lab results, physician or summary notes, admission and discharge summaries, etc.
Chart review studies can also be designed to collect prospective data, meaning the patient data does not exist at the time the protocol is submitted to the IRB for initial review. While many chart review protocols may qualify for a determination of exempt status from the IRB or expedited IRB review due to the minimal risk to research subjects, these studies are still subject to IRB review and HIPAA privacy protections. A guided and structured protocol-writing experience can accelerate the process while enhancing compliance, supporting collaboration, and saving time.
A chart review study protocol will generally include the following key elements:
- A synopsis — includes the objectives and high-level summary of the study elements, including a study flow chart
- Introduction and background — includes the protocol statement of compliance
- Rationale — includes the problem statement, risks and benefits
- Literature review — a synthesis of the current literature to establish the relevance of the problem and description of the literature that supports the need for the study
- Research design and methods — includes the study population and duration of the study. For chart reviews, a date range that indicates the timeframe for which records will be queried (e.g., a review of all ER visits between 1/1/2020 and 7/1/2020)
- Data collection and handling — includes a plan for maintaining subject confidentiality and privacy, how data will be collected and stored
- Statistical analysis plan — how the data will be analyzed to achieve the objectives
Chart review protocols are emerging as an important methodology in understanding COVID-19. Given the rapidly-developing nature of the global pandemic, the need for prompt writing and review of these protocols is critical to the ongoing effort to understand the situation.
ProtocolBuilder, a cloud-based research protocol-writing tool, can help improve the quality and consistency of clinical research protocols to make internal and IRB review processes more efficient.
Research Study Design
Research and HIPAA Privacy Protections (part of Comprehensive CIP Course for Advanced Learners)
BRANY’s IRB and Clinical Trial Services teams stand ready to support institutions and sponsors through COVID-19
Research institutions may need to transfer some or all of their clinical trials as they adjust operations in response to the coronavirus pandemic.
BRANY, a national organization that provides IRB review and clinical trial start-up services, announced today that its team of experts is standing ready to support institutions impacted by COVID-19.
Extraordinary measures, from “shelter in place orders” to ramping down non-essential services, have significantly disrupted IRB and clinical trial research operations. Front line health care providers are focusing their time and energy on myriad patient care issues. Clinicians who may have served on IRBs have necessarily shifted their focus to patient care. Meanwhile, research professionals, such as clinical research coordinators, are working from home, sometimes without the appropriate set-up or resources.
“Research institutions, hospitals and academic medical centers across the United States are all deeply impacted by the ongoing COVID-19 pandemic,” says Paddy Mullen, chief executive officer of BRANY. “We are a national company, owned by four academic medical centers in New York. Our deep expertise and knowledge of IRB and clinical trial start-up operations at academic medical centers, health systems, and hospitals, puts BRANY in a unique position to offer IRB and clinical trials support services that can be seamlessly incorporated into an organization’s day-to-day research operations.”
At this time, when staffing and resources for research oversight may be sparse, BRANY offers a seamless, integrated model of support. This may be particularly needed when research administrators may be pulled away from research oversight to tend to other organizational priorities. BRANY can support any institution, even those in a hardship situation, to help their IRB and Clinical Trial Offices remain compliant with regulations and institutional requirements.
“Several institutions are implementing investigator-initiated trials focusing on COVID-19,” says Ms. Mullen. “These urgently-needed protocols require swift IRB review, and we are positioned to provide that. We can also alleviate the burden of maintaining existing trials while resources are being redirected to COVID-19 trials.”
BRANY offers a wide range of research support services. Some organizations may need to temporarily transfer IRB oversight of some or all of their trials to ensure the protection of human subjects during this crisis. BRANY IRB is prepared to act as an IRB partner and assume IRB oversight. BRANY offers rapid clinical trial start-up services, including IRB review, budget development and negotiation, clinical trial agreement negotiation, and coverage analysis. BRANY also provides web-based technology solutions including SMART, a clinical trial management system, and Protocol Builder, a clinical protocol-writing application.
BRANY’s other divisions, CITI Program and the HRP Consulting Group, are also offering consulting, training and staffing support services to institutions facing a myriad of COVID-19 related concerns.
To discuss how BRANY can support an institution’s research needs, please contact Carmela Shabazz, Director, Corporate Development & Operations Support at 516-470-6979.
BRANY is a national organization providing a continuum of research and compliance support services to investigators, hospitals, universities and academic medical centers. BRANY was founded in 1998 by four nationally-ranked academic medical centers: NYU School of Medicine, Montefiore Medical Center, Icahn School of Medicine at Mount Sinai, and Northwell Health. BRANY IRB was the first IRB in New York to be accredited by AAHRPP in 2006.
Preparing for COVID-19 Impacts on Research Institutions
The rapidly evolving federal, state and local policies regarding COVID-19 are impacting every walk of life in the United States and around the world. Companies, as well as academic and government researchers, have pivoted their focus on vaccines and possible treatments for the novel coronavirus.
Health and research institutions are trying to keep up with rapidly changing policies and procedures, while still providing patient care in real time. Resources at medical facilities are being activated and redirected to respond to the increase in testing and treating patients.
Research institutions and sponsors are evaluating protocols to determine which ones may be paused, altered, or continued. A phase three clinical trial investigating a diabetes drug has been put on hold in order to protect patients and workers, according to the sponsor. Some universities have issued “urgent ramp-down of on-site, in-person research activities” or are downright “suspending all non-critical on-campus research activities.” Investigators are encouraged to check with their institutions’ research offices and sponsors for the latest information regarding trials in which they are involved.
Institutions must address several critical issues as they develop their policies, but the most important is the health and safety of patients and staff. Institutional review boards, research offices, laboratories and environmental health and safety committees must work together to provide guidance to investigators and research teams. These are some of the considerations in developing a policy:
- Flexibility — The situation is changing rapidly, as are federal, state and local mandates regarding the mobility of the public. In communicating with staff, it is important that they recognize and acknowledge the fluidity of the situation, and that policies may be revised in response.
- Continuity plans — Policies should consider continuity or contingency plans to protect the integrity of ongoing research. In some cases, disaster plans can be consulted for guidance in this situation.
- Communication with patients — Investigators and research offices will need a plan for communicating with patients and human subjects. Some institutions are waiving IRB review of these urgent communications.
- Reporting study deviations — IRBs will likely require reporting of study deviations, or have modified policies for doing so. Check with your IRB.
- Remote work contingencies — With many non-critical staff working from home, policies should address the use of video conferencing for IRB and other meetings, remote access and security of HIPAA-protected data, and so on.
- Telemedicine — Researchers may want to consider the use of telemedicine technologies to conduct study visits.
The rapidly changing landscape, the urgency and scale of response, and the impact on health care institutions is making this an unprecedented situation for everyone. Protecting the physical and emotional health of workers and patients should be at the center of our attention as we navigate uncharted territory.
Below are some resources for investigators who are conducting NIH-funded research:
National Institutes of Health
Global Impact on Clinical Trials
Taking Advantage of NIH Funding Increases for Investigator-Initiated Clinical Research Requires Thoughtful Protocol Writing
Earlier this year, the National Institutes of Health (NIH) announced the approval of a budget appropriation bill for funding through September 2020. In it, the NIH receives $41.68 billion in funding, an increase of $2.6 billion from FY 2019. For NIH, the new budget appropriation includes $500 million for the All of Us precision medicine study and a $25 million increase for HIV/AIDS research. It also included a $350 million increase for targeted Alzheimer’s research, $50 million to support pediatric cancer research, and $212.5 million to increase funding for adult cancer research.
The 2020 appropriation includes grant funding for both early stage and clinical research. One of the challenges in grant submission related to clinical research is developing a well thought out clinical trial protocol that can meet both scientific and regulatory requirements. Some investigators, particularly ones earlier in their career, may feel daunted by the process of writing a protocol.
Having an easy-to-follow, step-by-step protocol-writing tool can promote adherence to regulations and streamline the institutional review processes. Many institutions have developed protocol writing templates for investigators. Unfortunately, many of them are basic word processing documents and can be unwieldy and long, frustrating protocol writers. A cloud-based, guided experience can assist both seasoned protocol writers and those new to protocol writing, such as medical residents.
Physician investigators and medical residents are not the only ones who may benefit from such a tool. Doctoral students in nursing, physical therapy and other allied health fields are discovering that to complete certification in their fields, they must participate in clinical research.
Additionally, a cloud-based protocol writing system allows closer collaboration with co-investigators or research advisors. By engaging collaborators early in the protocol-writing process, investigators benefit from the shared ‘creative thinking’ that is critical to scientific development.
As institutions, including medical centers, support residents and early career investigators, they may wish to consider a more robust solution than Word templates. In identifying and selecting a tool, they should consider the following questions:
- Does the tool allow easy collaboration with mentors or co-investigators?
- Is it a guided experience, offering assistance and education throughout the process?
- Can it be customized to suit the requirements of the individual institution?
- Does it maintain an audit trail of changes?
These and other critical questions can help institutions evaluate the best protocol-writing tools. By supporting investigators in medicine and allied health fields, institutions can realize the benefits of clearly-articulated protocols. This, in turn, may help increase opportunities for developing well thought-out investigator-initiated clinical protocols that can help strengthen a grant submission.
Challenges and questions remain as the one year anniversary of the implementation of the Revised Common Rule approaches
One year has passed since the implementation of the Revised Common Rule, and many challenges and questions remain. While IRBs wait for promised guidance to materialize, we are left to interpret various aspects of the rule ourselves. This has resulted in variability across IRBs in how the new requirements are interpreted and operationalized.
Variability in the Key Information Summary
A significant area of confusion and variability relates to informed consent. The Revised Rule requires that “informed consent must begin with a concise and focused presentation of key information that is most likely to assist a prospective subject or legally authorized representative (LAR) in understanding the reasons why one might or might not want to participate in the research.”
Overall the response to the requirement for the Key Information section has been positive among IRB members since it provides an opportunity to highlight the most important information. However, significant challenges remain. IRBs have come up with a wide variety of approaches to meet this new requirement, ranging from brief paragraphs to lengthier, organized tables of information.
In our experience, industry sponsors have also not uniformly grasped the intent of this section, which is meant to be concise. Sponsor representatives often cut and paste long, complicated sections of risk language from the main body of the consent document (often multiple pages worth). This creates complex key information sections, resulting in more work for those who prepare consent documents, and more back and forth with sponsors.
Broad Consent Poses More Questions
Some additional informed consent issues that have been problematic relate to the provision of “clinically relevant research results” and under what circumstances they should be provided back to subjects, the statement regarding future use of research specimens, and the required element regarding whole genome sequencing.
Although the broad consent option was intended to give researchers better options for obtaining consent to use information and specimens for research, the fatal flaw seems to be the requirement to track refusals. Given the final rule’s definition of what was identifiable, and the removal of the concept that all biospecimens are identifiable, the need for a mechanism such as broad consent was diminished. As a result it seems that institutions are not utilizing the new broad consent option.
Institutions, particularly large medical centers with multiple facilities, still need guidance on how to operationalize the mechanism of broad consent. How far does the refusal to broad consent have to be tracked? What if an individual visited multiple facilities and gave conflicting answers to the request for broad consent? What if an individual changes their mind? Broad consent does not appear to be a great option for most research institutions at this point.
Navigating the Transition
For IRBs that have not transitioned studies that were approved prior to January 21, 2019 to the Revised Rule, another challenge is having two sets of rules to follow, as some studies fall under the pre-2018 requirements, and others under the 2018 requirements. An additional complicating factor is the lack of harmonization with FDA regulations. For many, their systems had to be customized to allow for labelling of studies so it is clear which regulations are applicable to a particular study. IRB reviewers also need to be particularly cognizant as they review multiple studies for one meeting, as there is no one set of rules to follow.
The transition to the revised Common Rule has been challenging to a community that worked under rules that remained largely unchanged for several decades. While the changes were definitely needed, and welcomed by most, there will be growing pains. As exemplified by some of the scenarios above, some areas will need to be refined as we gain experience in applying the new rules. While we patiently wait for guidance and harmonization, IRBs continue to do a magnificent job of sharing best practices among each other. At the end of the day IRBs seek to protect the rights and welfare of research participants, despite any hurdles that come along.
The Critical Issues Sites Need to Track During a Clinical Trial – Part Three – Enrollment
Congratulations! You have gone through all the necessary steps to launch a clinical trial. Now it’s time to move on to the next one, right? Wrong! A successfully managed clinical trial requires ongoing tracking throughout its duration. Careful tracking ensures your research organization remains compliant and that your site is compensated properly for the study.
Follow our series on the key critical issues you need to track throughout a clinical trial.
Part Three — Enrollment
One of the most pressing reasons why clinical trials are delayed is low enrollment. According to a Tufts University study, nearly half of clinical trials do not meet their participant enrollment goals.
Many of these challenges need to be addressed before a site determines that they will participate in a clinical trial. A realistic assessment, or feasibility study, of a site’s enrollment potential can minimize the risk of low enrollment later. The assessment may include an evaluation of your patient population, community demographics, prevalence of the disease being studied, and so on.
Enrollment and Sponsor Billing
Accurate enrollment tracking is directly tied to the ability to invoice study sponsors, which has an impact on cash flow for your site.
Typically sites provide data to study sponsors in real time when they enroll participants and when participants complete study visits and procedures throughout the course of their participation in the study. Sites should also be tracking their enrollment information internally at least monthly, and comparing the actual number of participants enrolled against what was originally estimated. Regular tracking allows a site to notify the study sponsor of possible problem areas early in the process, when enrollments seem to be falling behind original targets. If other sites are experiencing difficulty meeting enrollment targets an intervention, such as a protocol amendment, may be necessary. Coaching on recruitment techniques could also be helpful.
Include “Screen Failures”
The number of enrolled study participants is not the only critical metric. Sites should also track the number patients who go through the screening process, but for some reason are not qualified to participate in the study. These are called “screen failures.” Often sponsors will include a certain amount of reimbursement in the study budget for screen failures, Therefore it is important to track and invoice sponsors in accordance with the study budget.
Additionally, a high number of screen failures can signal an issue with the protocol’s inclusion and exclusion (eligibility) criteria. A screening log that includes information about the reason for exclusion can be important in a “root cause analysis” if enrollment goals are not being met.
Not only is it important to track initial enrollment, but sites need to monitor retention, or when a patient drops out of a study for any reason. Dropout rates can have implications for analysis. Having an “early warning” system in place to identify high dropout rates gives sites the opportunity to mitigate the problem.
Tracking the study procedures for participants who may terminate from the study early is also important. Sites should be paid for all study procedures performed up to the point of termination.
Besides the budget implications, a site can gain critical insights in tracking detailed enrollment data, which can then aid them in making future decisions about participating in trials. These “lessons learned” can assist a site in being more successful in future clinical trials.
The Critical Issues You Need to Track During a Clinical Trial
Congratulations! You have gone through all the necessary steps to launch a clinical trial. Now it’s time to move on to the next one, right? Wrong! A successfully managed clinical trial requires ongoing tracking throughout its duration. Careful monitoring ensures your research institution remains compliant and that your site is compensated properly for the study.
Follow our series on the key critical issues you need to track throughout a clinical trial.
Part Two — Budgeting and Maximizing Revenue
Research sites that have a clear process for clinical trial budgeting as well as billing and collections can ensure their research efforts are feasible and sustainable.
An initial process that thoroughly accounts for every expense related to the clinical trial will result in a thoughtful budget that supports site resources. In addition to completing a Coverage Analysis to determine research procedures from standard of care procedures, research coordinators should consider costs that may be “hidden” or less obvious such as protocol specific training, or time needed for site initiation and monitoring visits. A detailed budgeting process up front will make tracking study activity and expenses much easier. Besides the expenses related to patient visits, budgets should include line items that cover time and effort of the investigator, the coordinator, and other research personnel for the various administrative tasks necessary to effectively carryout the requirements of the study. These administrative tasks can include:
- Screening for eligible participants
- Responding to sponsor queries
- Reviewing safety reports
- Preparation of regulatory documents or maintaining the regulatory binder
Throughout the study, it is important to track not only visits and procedures, but also items for which you need to invoice the study sponsor or CRO. Invoiceable fees can include procedures done outside the study visits, such additional scans, lab tests, or unscheduled visits. If patients are reimbursed for travel or other expenses, these should also be tracked.
To ensure research billing and collections are maximized it is essential to have strong systems in place to track all study visits and procedures completed throughout the study and record all the activity in comprehensive invoices. It is also important to track study payments and accounts receivables. Reconciling payments received from the sponsor/CRO to the study budget and to the actual study activities completed is critical. If you do not receive payment for all study activity your cash flow and profitability are impacted.
Careful tracking of all study activity, billable expenses, and sponsor/CRO payments help ensure that your site will have positive cash flow and cover its costs related to operating clinical trials.
The Critical Issues Sites Need to Track During a Clinical Trial
Congratulations! You have gone through all the necessary steps to launch a clinical trial. Now it’s time to move on to the next one, right? Wrong! A successfully managed clinical trial requires ongoing tracking throughout its duration. Careful tracking ensures your research organization remains compliant and that your site is compensated properly for the study.
Follow our series on the key critical issues you need to track throughout a clinical trial.
Part One — Protocol amendments
This is likely one of the most common and time-consuming of the issues that require tracking. A Tufts University study found that over half of sponsored studies have at least one significant amendment.
Protocol amendments are inevitable, and some trials undergo multiple amendments throughout their duration. But some revisions are so significant it could feel like starting all over again.
There are generally two kinds of protocol amendments — administrative updates and substantive protocol revisions. Administrative changes are typically minor, and may involve grammar, wordsmithing, punctuation or small editorial changes. Significant amendments are any changes that may impact the safety of participants, and can include any change to the design of the protocol, including:
- Change to the dosing or duration of participant exposure to a drug
- Change to the design of the protocol, such as the inclusion or exclusion criteria or the addition of treatment arms
- Addition of new tests or procedures
IRB review and approval is required in order to carry out the visits and procedures that are part of the amended protocol. IRBs often require the following information when submitting an amendment:
- A description of the differences between the original protocol and the amendment
- Revisions to the informed consent, if applicable
- Revisions to any marketing or patient recruitment materials
Protocol amendments can impact patient recruitment efforts. In fact, some protocol amendments may also affect a site’s ability to enroll if there are significant changes to inclusion or exclusion criteria. Often the consent form must also be revised to reflect the changes to the protocol. Patients may need to be re-consented with the updated, IRB approved version of the consent form so they can be made aware of changes in protocol procedures.
Depending on the scope of the protocol amendment, your research site should review the study budget, as the necessary procedures may have changed or new procedures and visits may have been added. In our experience, amendments have an impact in roughly half of all study budgets. A full review of the budget, and possibly a revised Medicare Coverage Analysis, may be necessary.
Create a checklist
The more you prepare and plan for protocol amendments, the smoother the process to implement the amended protocol. The use of a checklist or systematic approach will ensure that no steps are overlooked.
Whenever there is a protocol amendment, clinical research coordinators should make sure they update the following:
- IRB/IEC and other regulatory submissions
- Informed consent documents, including oral consent scripts
- Marketing, advertising or recruitment materials
- Sponsor contract, particularly if there is an impact to the budget, and coverage analysis, if applicable
Studies have shown that protocol amendments can impact the cost and duration of clinical trials. But with some careful preparation, clinical research coordinators can ensure a smooth administration of the changes.
News Release – BRANY Names Michael Belotto as Chairperson for Social-Behavioral IRB
BRANY (brany.com) has announced that Michael Belotto, PhD, MPH, CCRC, CCRA, will serve as chairperson for their social-behavioral IRB. The SBER IRB is comprised of a multidisciplinary group of experts in social and behavioral research, as well as human subject protection.
“Dr. Belotto has been a great contributor to BRANY IRB’s success over the past 20 years,” says Raffaella Hart, MS, CIP, Vice President, IRB and IBC Services for BRANY. “In serving as an IRB member and Quality Assurance auditor, he has been dedicated to ensuring that investigators conduct research in compliance with federal regulations and ethical guidelines. Researchers and research participants will be well-served with Michael serving as the Chairman of BRANY SBER IRB.”
BRANY started the SBER IRB in 2016 in response to an unmet need identified by social, behavioral, and education researchers. Common feedback from this group of researchers centered on the fact that most IRB processes and procedures were rooted in biomedical research which often did not align with the needs of social and behavioral researchers. The issues in social-behavioral research are distinct from biomedical research in a variety of critical ways, and need the review of experts in the relevant fields. Research protocols can include graduate student dissertations, research outside the U.S., as well as focus groups.
Dr. Belotto serves as a research compliance expert responsible for auditing sites to ensure investigators’ compliance with FDA regulations and ethical guidelines. He will continue to serve as a member of BRANY IRB in addition to chairing the SBER IRB.
Dr. Belotto worked as a paramedic in the New York City Emergency Medical Service 9-1-1 system for 10 years, with 7 years of experience in Hospital Administration.
Dr. Belotto is a graduate of New York Medical College where he completed a Master’s in Public Health with a concentration in epidemiology. He completed his doctorate in Public Health at Walden University.
The SBER IRB is part of BRANY’s Connected IRB model, which helps maintain an ongoing connection among investigators, institutions and the IRB, by promoting communication with key stakeholders. This includes email alerts for investigators and research coordinators as well as specific alerts for critical concerns such as unanticipated problems involving risks to subjects or others.
The Revised Common Rule and New “Concise Summary” Requirements
Our own Linda Reuter offers thoughts on how to meet new ‘concise summary’ requirements on informed consent for clinical trials. https://bit.ly/2JUQ8o3
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.
Is This the Right Study for Your Research Site? Five Questions You Should Ask Before Agreeing to be an Investigator
Clinical investigators often have multiple opportunities to participate in sponsored clinical trials. In addition to the professional satisfaction of being at the forefront of therapeutic development, clinical trials present an ability for physicians to offer patients alternatives to treatments they may otherwise be unable to access.
While study sites may receive compensation for time and resources invested in starting up and running a clinical trial, it is important to recognize exactly how much of an investment is required of study sites to be successful. Additionally, sites may invest time and resources only to discover that the trial is delayed or terminated due to issues of enrollment and other challenges.
Clinical trial delays may suffer from a variety of root causes, but participant enrollment is often cited as one of the most significant. Investigators must be realistic about their practice’s ability to recruit and enroll participants within the prescribed timelines. The ability to meet sponsors’ expectations is essential in maintaining positive relationships, which can lead to future opportunities.
Assuming the research has scientific merit and is ethical, investigators need to be realistic about their capacity before deciding to join a clinical trial. By carefully reviewing the proposal from the sponsor, and balancing the requirements of the protocol and expectations of the sponsor against the capacity of the practice, investigators can increase their chance of starting and running a successful trial.
Before agreeing to participate in a particular study, these are five questions every investigator should answer.
Do I have sufficient staffing available to execute the trial within the timelines set by the sponsor/CRO, in compliance with the protocol, and in accordance with regulatory requirements?
As studies become more complex, the time and resources necessary to start up and run clinical trials increase. It is important for investigators to have a conversation with their clinical trial staff about their workload. You may need to consider adding capacity by outsourcing administrative processes to supplement your existing staff resources.
Do I have the appropriate and sufficient patient population from which to draw participants?
Carefully review the inclusion and exclusion criteria in the protocol. If possible, run a query through your EMR to see the approximate number of potential patients that might be eligible to participate. If you do not have sufficient patients in your practice, how will you expand your enrollment efforts to the broader community?
Do I have other ongoing studies that may compete for enrollees among the same patient population?
With each clinical trial in a particular therapeutic area, your pool of potential enrollees may decrease. Carefully review your current clinical trial commitments to ensure you are not spread too thinly across a narrow patient population.
Do I have the infrastructure to support this study?
If you add staff to help with the trial, you should consider space issues. (Of course, if you have outsourced administrative duties, this is not a consideration.) Additionally, you should think about drug storage, archive space, space for documentation files, and equipment. Study monitors also need a desk or conference room when they are on-site monitoring the trial. Finally, what is your institution’s laboratory and pharmacy capacity?
Do I have the necessary credentials and expertise to conduct this trial?
Ensure that your certifications, such as Good Clinical Practice (GCP), etc., are up to date. Be prepared to provide evidence of your clinical expertise in the specialties or therapeutic areas of the study.
Investigators should agree to take on new research projects only when they can carry out the research in an ethical manner in full compliance with all regulatory requirements, as well as meet the expectations of the study sponsor. A realistic assessment of personal, practice and institutional capacity will help ensure that you are participating in appropriate trials.
Four Essentials for Clinical Trial Enrollment
Clinical trial enrollment continues to be one of the most vexing challenges for research institutions and sponsors. Despite one quarter of sponsors’ clinical trial budgets being allocated to enrolling participants, half of research sites enroll only one or no patients in studies. Recruiting a diverse patient population is an even bigger challenge, with ethnic minorities, women and the elderly often underrepresented in clinical research.
Typically a contract between an investigator and the sponsor will outline the number of participants to be enrolled. The inability to enroll the required number of patients can have serious implications for the study’s success. Eighty percent of clinical trials fail to finish on time and 85 percent fail to retain enrollees, leading to canceled trials. Not meeting enrollment targets can dampen the relationship between the investigator and the sponsor and perhaps diminish future opportunities for the research site.
The vast majority of patients are willing to enroll, if only they know it’s an option. Eight-five percent of patients were either unaware or unsure that they could enroll in a trial, according to a Harris Interactive Survey of cancer patients. But 75 percent of these patients said they would have been willing to enroll had they known it was possible.
Sponsors are turning to artificial intelligence, machine learning and other technologies to provide detailed predictive analytics in an effort to improve recruitment. These technologies can comb through thousands of electronic medical records and other demographic data, and cross-reference criteria from hundreds of available trials. Microsoft just announced a chatbot designed to match patients to trials.
Sponsors must continue to work closely with research sites to coordinate the most effective methods of finding and enrolling patients, however. Even with new technologies, research coordinators and investigators play the most important roles in the successful recruitment and retention of clinical trial participants. By nurturing relationships in patient communities, a human-centered approach can yield demonstrably improved results.
Budget for recruitment. Recruitment and enrollment takes the time of the research coordinator and other staff—time that needs to be accounted for in the study budget if the research institution is to avoid working at a loss. When budgeting, consider the entire process of patient recruitment, not just the advertising budget, to ensure an accurate assessment of resources used.
Collaborate with colleagues. Investigators and research coordinators should network and collaborate with their colleagues in other specialties, and leverage these relationships to encourage patient referrals to clinical trials. Many clinical trials cross over different specialties. For example, a study may encompass both cardiology and endocrinology for heart disease and diabetes. Creating a network, even an informal one, to share ideas and proactively discuss clinical trials with their patients will raise awareness.
Understand the compliance issues. Compliance issues impact patient enrollment in a variety of ways. For example, if you will be reviewing medical records to identify potential research participants, you may need a partial HIPAA waiver for recruitment purposes from the IRB to share information.
Compliance also impacts any traditional advertising and marketing. Sponsors may sometimes run larger national awareness campaigns for certain clinical trials, but for others it’s often up to the investigators to reach out within their own community through traditional advertising methods. This can include newspapers, radio and local cable television. It can be as simple as distributing flyers in places where potential participants may see them. Whatever media you use, the IRB needs to review the material before it is released. Physician-to-physician letters may not require IRB review so check your IRB’s policies in advance. Consider advertising a step in your recruitment plan.
Monitor progress. In the course of running a busy clinical practice, it may be easy to let your recruitment efforts slip. At the beginning of the trial, schedule regular “touch base” meetings with your team to learn what you are doing to recruit participants and how successful those efforts are. If an activity is not yielding results, you can replace it with something else and not waste unnecessary time and effort.
Technologies are moving rapidly in artificial intelligence and machine learning. Staying abreast of these developments and trends can keep you ahead of the curve and aware of opportunities for your practice. However, personal relationships and human contacts are still an essential part of the patient recruitment toolkit.
 Clinical Leaders
Reconciling Your Clinical Trial Protocol Start-Up Costs and Budget
As clinical trials protocols have grown more complex and more disparate teams are working on different elements of executing them, there is a potential for incongruency between the protocol requirements and the budget. It is critical to engage the stakeholders that will have a part in carrying out the research in the budgeting process. All departments must ensure their costs related to facilitating the research will be addressed in the study budget. Failing to include key stakeholders in the process can lead to financial losses or a lack of commitment from stakeholders that are critical to successfully achieving the established goals for the study.
Even if a site is diligent about including ongoing costs such as the procedures associated with each patient visit, pharmacy costs, and radiology costs, some of the start-up costs may be overlooked. These are some of the key areas of risk in developing a budget.
Before a study even starts, research sites will incur certain expenses related to site selection activities, and training staff on the study protocol. Even items such gaining access to the sponsor’s web based portal can require the support of IT to adjust system configurations that permit access to such portals.
It may seem minor, but the time and effort it takes to develop a budget should actually be in the budget. In fact, other activities required for start-up, such as meetings with other departments and coordinating the start-up paperwork, should also be part of the overall administrative budget.
The preparation and review of consent forms is also a cost often overlooked.
For example, a research site may need to translate consent forms into different languages (depending on the community it serves) for non-English speaking participants.
Not every patient is qualified to participate in a clinical trial, so there are screening costs. Your site may have to screen several people for each person who actually gets into the trial. These are called “screen failures,” and they take time and effort.
In addition to ongoing training of staff, certain protocols may require specific additional training to ensure compliance or appropriate recruitment of patients.
Other department costs
Does your clinical or research lab, or pharmacy, have start-up costs to prepare for the initiation of this clinical trial? Investigators should understand the implications for other departments on whom she is dependent for the successful launch of the trial. Other costs to consider in the budget for other departments are annual maintenance fees and close out fees.
The research coordinator needs to prepare documents for IRB review. Even if your site uses a local IRB, those fees should be included. You may also want to include an annual or quarterly fee to cover staff time for management and maintenance of the research project and submission to the IRB for continuing review approval.
It is critical that an investigator or research coordinator understands all the tasks and procedures that impact the execution of research protocol and develops a complete and accurate budget. The sponsor’s template budget will not generally include all the budget elements, especially those related to administrative start-up, which may not be obvious. Carefully review all protocol related costs, discuss the protocol with key stakeholders, and be prepared to negotiate with the study sponsor to secure the fees needed to cover the study costs.
Burnout Among Research Coordinators — Warning Signs and How to Avoid Them
Let’s face it. Every job has its challenges. However, burnout seems to be at an all-time epidemic level. A recent report from Harvard University highlighted physician burnout as a public health crisis. A keyword search for “preventing burnout” yields 15 million results in Google. In the United States, problems associated with burnout are estimated to cost more than $120 billion a year.
Burnout is typically defined as a response to prolonged stress. Key signs are emotional exhaustion, cynicism or detachment, and feeling ineffective. The results can include a feeling of isolation, irritability, and even frequent illness and absenteeism. One study indicates that up to eight percent of annual healthcare costs are associated with and may be attributable to how U.S. companies manage their work forces.
Research coordinators, too, face burnout that may be resulting in high turnover rates, low enrolling studies, disrupting workflows and even delaying the start of clinical trials. Certainly at many institutions, risk factors are in place for research coordinators to experience burnout — increased workloads, few opportunities to learn, lack of feedback and limited autonomy.
There are thousands of articles and blog posts about preventing burnout, often putting the impetus on the individual. Many articles cheerily extol professionals to “find life work balance,” eat a balanced diet, exercise or get some sleep. Preventing burnout is not the sole responsibility of the individual to self-manage. There is a vast database of scientific research on workplace predictors of employee burnout. The reality is that organizational culture is a primary driving cause of burnout.
Here are some steps your organization can implement to reduce the risk of burnout and increase motivation and engagement among research staff.
- Offer ongoing professional training. The field of clinical research is constantly shifting, with the regulatory landscape increasingly complex. Professional training increases competence, which improves performance.
- Look for opportunities to provide autonomy. With training, research coordinators can have the appropriate knowledge and confidence to manage some workplace decisions. This is especially the case in places with high workload and emotionally demanding clients, such as patients. And while research coordinators are often extremely independent in their work style, researchers must remain diligent in keeping lines of communication open and regularly meeting with their research team.
- Provide feedback. Researchers and clinicians are busy, also, dealing with their own job stresses. Despite this, clinical research coordinators and other research staff benefit from receiving constructive feedback, including explicitly expressed appreciation from senior leaders.
- Be realistic about workload. Every job has its times of increased demands. But if daily workload transforms into a chronic overload, there can be serious implications. Leveraging outsourced solutions can ease some of the pressure when overload situations arise. Partnering with outsourcing service providers that can work as an extension of your institution, can complement the internal staff responsibilities.
Given the negative impact of burnout on individuals’ well-being and workplace performance, it is critical that organizations seek proactive ways to create cultures that support and engage their staff.
Aligning Timelines for Better Coordination
Increased complexity of launching and running research protocols means different teams are contributing their expertise to ensure human subject protection, accurate budgets and successful patient recruitment. It also means that, with so many disparate groups involved, the risk of delays increases.
One significant contributor to delays in study start-up is the lack of a common understanding for the overall timeline. Each group may know what it is responsible for, but may not be aware how its actions impacts others. An IRB approval can be in place for months while another team still wrestles with the budget or contract with the sponsor. This disconnection can lead to lengthy study start up times and put an institution at a disadvantage in achieving success in its research programs
These are a few best practice tips for keeping everyone on track:
- Appoint a quarterback. Even if your institution does not have a centralized approach to study start-up, it’s critical that at least one person is responsible for setting the calendar, communicating with different teams and setting expectations. This requires having a general understanding of the processes of different committees, such as the pharmacy or radiation safety committee.
- Create a master calendar. Developing and sharing a master calendar, including dependencies, is a fundamental pillar of successful project management. This should include the schedule of all committee meetings. This kind of “big picture” calendar helps identify if there are risks to the schedule. Ideally key stakeholders in the start up process (Investigator, Coordinator, CRO, Sponsor) will collectively decide on a timeline consistent with industry expectations. Do we want to say suggest a completion date goal and share it w the sponsor?
- Have regularly scheduled check-in meetings. Depending on the volume of your studies, this can be a weekly meeting with representatives of each of the teams or committees to discuss the status of each and identify risks of delay. This gives everyone an opportunity to understand the impact of one team on the whole. As an added bonus, this kind of collaboration across teams can encourage creative problem solving to get past hurdles.
- Schedule regular email updates. Yes, we have too much email. But a weekly, perhaps every Monday morning, email to everyone on each of the teams that outlines what is critical that week, will keep everyone on track. This builds transparency to the process and creates accountability.
- Coordinate with the sponsor. There are times when a sponsor is unaware that a research site has reached a particular timeline milestone, which can impact their ability to provide needed information. Sponsor processes also need to be connected to the timeline.
The two most important factors in ensuring on-time clinical study start-up are transparent communication and team accountability. These coordinated best practices can help to ensure a successful, on-time program.
Are Staffing Challenges Affecting Your Institution’s Research Profile?
Many institutions still struggle to recruit and retain the best talent for these challenging positions. A changing regulatory landscape, increasingly complex protocols and a litany of deadlines all contribute to a stressful environment for these employees. Additionally, salaries have remained largely stagnant, creating a general sense of disengagement.
Staff turnover can lead to interruption in workflow and management, often creating delays for study start-ups. With study coordinators often the primary contact with CROs, regulatory agencies and sponsors, the disruption and inconsistency in communication can have a negative impact on the relationship with these important stakeholders.
“We have seen situations at institutions in which an entire study was put on hold because a coordinator departed and there was no one to continue the work,” says Jill Filipelli, BRANY’s Clinical Trials Activation Team, Operations Manager, “This created quite a bit of consternation and frustration from the sponsor.” These institutions are at risk of losing future opportunities as selected study sites.
High turnover can be expensive for employers. A study published by the Society for Human Research Management showed that replacing an employee can cost up to 50 to 60 percent of the employee’s annual salary. If you add the cost to onboard and train a new coordinator in procedures and protocols, the cost of recruiting a new employee can be significant. Investing in retaining experienced talent can save in long-term costs associated with turnover.
Studies have shown that salary alone is not the key factor in retaining staff. According to a 2012 Centerwatch study, study coordinators are looking to advance their careers through professional training and promotions. Providing opportunities for education and training is a cornerstone to a successful staff retention strategy. Ongoing mentoring of CRCs can also encourage more engagement and job satisfaction.
Investing in the development of clinical research staff can yield results well beyond mitigating the hassle of hiring new employees. Having a consistent team also ensures consistency and smoother workflow to ensure the successful start-up and management of clinical research programs. This, in turn, stabilizes and improves relationships with CROs and sponsors when they are identifying research sites.
The Revised Common Rule and Informed Consent: Public Posting
An important provision in the Revised Common Rule is the requirement to post, to a publicly-available federal Web site, a copy of an IRB-approved version of the consent form that was used for enrollment purposes for each clinical trial conducted or supported by a federal department or agency. The Office for Human Research Protections (OHRP) has identified two publicly available federal websites that will satisfy the consent form posting requirement in the revised Common Rule: http://ClinicalTrials.gov and a docket folder on http://Regulations.gov. It is possible that additional sites may be identified in the future.
The consent form will need to have an up-front concise and focused presentation of the key information as required by 46.116(a)(5).
The specific requirement is that an IRB-approved consent form that was used for enrollment purposes be posted. There is no requirement to post multiple forms for multicenter studies, or for a study that has separate consent forms for different subject groups (e.g., adults versus pediatric participants). Also, for consent forms that underwent revision over the course of the study, the final rule does not stipulate that the posted document be the most recently approved version.
The posting can take place any time after the clinical trial is closed to recruitment, and no later than 60 days after the last study visit by any subject, as required by the protocol. Information that should not be made available on a federal website, as determined by the federal department or agency supporting or conducting the clinical trial, can be redacted.
The purpose of the new provision is to increase transparency, which some feel will lead to improved consent form quality. The commentary to the Final Rule, describes how having an easily accessible repository of such forms freely available for analysis and public discussion will foster public discussion and create multiple opportunities for improving these forms, and thereby improve one of the most important aspects of our human subjects protections system.
For More On The Revised Common Rule and Informed Consent, see our previous article on Consent Waivers
The Revised Common Rule Compliance Dates and Transition Provision Draft Guidance
The Department of Health & Human Services (HHS) has released The Revised Common Rule Compliance Dates and Transition Provision Draft Guidance. In it, you will find information about transitioning studies to the Revised Common Rule, and answers to frequently asked questions. Our team at BRANY has been closely monitoring the guidance from regulatory agencies and is prepared to help our clients in this transition period.
The Revised Common Rule and Informed Consent: Consent Waivers
The Revised Common Rule has a few important changes regarding consent waivers.
Under the revised Common Rule, broad consent is provided as an alternative to the informed consent requirements for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens. If an individual was asked and refused to provide broad consent, the IRB is prohibited from waiving informed consent at a later date for the use of the subject’s identifiable private information or identifiable biospecimens in a secondary study. This means that this information must be tracked. This may be complicated, particularly for larger health care institutions and systems, and therefore the broad consent mechanism may not be widely utilized.
Of note is that the use of the individual’s materials in a nonidentifiable manner in secondary research continues to be permissible, even if there was a refusal to broad consent, since this particular use would not otherwise require a waiver of informed consent since the activity does not constitute research with human subjects.
The Revised Common Rule also adds a new waiver criterion. In order to waiver or alter consent, the IRB must find and document the following:
- The research involves no more than minimal risk to subjects;
- The waiver or alteration will not adversely affect the rights and welfare of the subjects;
- The research could not practicably be carried out without the requested waiver or alteration;
- (New as of January 21, 2019) If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format; and
- Whenever appropriate, the subjects or legally authorized representative will be provided with additional pertinent information after participation
The term “practicably” has not been clarified in the revised rule.
In the case of recruitment and screening of research subjects, the pre-2018 rule required an IRB to determine that informed consent can be waived under the .116(d) criteria before investigators could record identifiable private information for the purpose of identifying and contacting prospective subjects for a research study. Although not considered a “waiver,” under the new rule, an IRB can approve an investigator’s proposal to obtain information directly from a prospective subject, or to obtain already collected identifiable information or identifiable biospecimens by accessing records or stored biospecimens, for purposes of screening, recruiting, or eligibility assessment, without the informed consent of the prospective subjects.
The Revised Common Rule’s section on waivers or alterations of consent can be complicated, so it is important for research professionals, researchers and IRBs to review the changes and the exceptions.
For More On The Revised Common Rule and Informed Consent, see our previous article on Broad Consent
The Revised Common Rule and Informed Consent: Broad Consent
While the industry waits for additional guidance on the Revised Common Rule, there are some aspects that are worth taking note now. This is a series of blog posts that address various important changes for research professionals to keep in mind as they implement the Revised Common Rule.
BLOG POST #2 — Broad Consent
One of the significant changes in the Revised Common Rule is the introduction of Broad Consent., a new type of consent intended to serve as a substitute for traditional informed consent in certain circumstances. “Broad Consent” is a very specific term in the revised regulations used to describe a regulatory pathway, and is different from the concept of obtaining consent for future use of information or specimens under the prior regulations.
The new regulations also provide two new exempt categories for the storage, maintenance and research use involving identifiable private information or identifiable biospecimens when broad consent has been obtained.
Broad consent may prove to be problematic, particularly for large medical centers or health care systems, due to the documentation requirements. The regulations stipulate that an IRB cannot waive consent for storage, maintenance, or secondary research use of the identifiable information or identifiable biospecimens if an individual was previously asked to provide broad consent and refused. Such tracking requirements may make broad consent very difficult to implement, and may limit its usefulness.
A Broad Consent Form must contain certain elements in order to be valid. The following elements are unique to broad consent, and must be included:
- A general description of the types of research that may be conducted with the information or biospecimens that a reasonable person would need to make a determination
- A description of the identifiable information or biospecimens that might be used in research, whether sharing might occur, and the types of institutions or investigators that might conduct such research
- A description of the period of time allowed that the information or biospecimen would be stored and maintained or used for research purposes (may be indefinite)
- Statement that the subject or LAR will not be provided details about specific research studies that might be conducted using the information or biospecimens including the purposes of the research and that they might have chosen not to consent to some of those specific research studies
- Results may not be disclosed to subjects
- Contact information for questions about rights and storage and use of the information and specimens, and whom to contact if the event of a research-related harm
These elements are required in every broad consent document, and cannot be waived.
For More On The Revised Common Rule and Informed Consent, see our previous article on Concise Summary
The Revised Common Rule and Informed Consent: Concise Summary
While the industry waits for additional guidance on the Revised Common Rule, there are some aspects that are worth taking note now. This is a series of posts that address various important changes for research professionals to keep in mind as they implement the Revised Common Rule.
Consent forms must facilitate comprehension by providing information that a “reasonable person” would understand in order to make an informed decision about whether or not to participate in a clinical research protocol. This includes a brief summary that is concise, focused and includes the key information about the research.
So far there has been very little guidance on the length or specific required content of the summary. It likely depends on the study itself, as well as the patient population that is being asked to participate. This will allow for flexibility in what is included in the summary.
The summary can refer to information included later in the consent, which provides the full context of a study, including its risks and benefits. Generally speaking, these five factors will most likely assist a “reasonable person” in making a decision about study participation:
- The fact that consent is being sought for research and that participation is voluntary
- The purposes of the research, the time commitment that will be expected, and the main procedures
- The most common risks or discomforts to the prospective subject
- Benefits to subject or others that are reasonably expected
- Alternative procedures or courses of treatment, if any, that might be advantageous
- Any significant costs that will be incurred
These new guidelines apply to all federally supported studies, and may also apply to other studies depending on how each institution applies the requirements of 45 CFR 46 across the board to all studies.
It will be important to note in the summary that the key information that is presented up front does not include all of the information related to the study. Potential subjects will need to be advised that in order to have all the details about the study and their participation in it, they will need to refer to the full consent form and also discuss any questions or concerns with the study doctor during the consent process.
Career Series: Late Career
Experienced Research Professionals Should Consider Mentoring the Next Generation
Approximately 10,000 baby boomers will turn 65 every day between now and 2030, according to a study by the Pew Research Center. The field of clinical research is no exception to this enormous wave of research leaders reaching retirement age and exiting the profession.
As senior research professionals turn toward their retirement, now may be a good time to consider how they may leave a legacy. Mentoring can enrich the work lives of both mentor and mentee through sharing of knowledge, skills, insights and wisdom. The profession also benefits by developing emerging leaders to take on new responsibilities. Mastering how to navigate through the regulatory landscape that governs research is difficult, and having the chance to learn from those that have mastered this field will make a huge difference to the future of the industry.
Developing a dedicated pipeline of leaders
According to Price Waterhouse Coopers, millennials will make up over half of the workforce by 2020. There is an enormous opportunity to demonstrate the importance of the research mission and how its benefits to society can lead to a career of meaningful work. These two areas are important to the next generation of workers, according to several surveys.
But how does one become a mentor? Beyond being a teacher or advisor, a strong mentor also understands the interpersonal part of the relationship based on an understanding of the mentee, and a willingness to invest emotionally in a mentee’s growth and development.
Rather than focusing on teaching or dispensing advice, it’s useful for the mentor to listen, ask questions and demonstrate a curiosity about what motivates the mentee. Sometimes it can be more meaningful and a stronger learning experience if the mentee is guided to his or her own answers to questions.
Lead by example
Being a role model — by demonstrating the skills and emotional intelligence necessary to be a successful research professional — can teach important lessons in navigating an institution or the profession.
A strong mentor will nudge a mentee into reaching for goals beyond the status quo. Having a clear understanding for a mentees strengths and capabilities can help a mentor understand the person’s potential.
Being a mentor can be part of developing a formal succession plan in order to fill the open leadership positions with passionate and talented workers. Such planning should include providing ample training opportunities.
With a few guidelines, a mentor and mentee can both benefit from a rich relationship.
Data Analysis Methods for Qualitative Research: Managing the Challenges of Coding, Interrater Reliability, and Thematic Analysis
The peer-reviewed journal The Qualitative Report has published an article by Michael Belotto, Director of the BRANY Institute of Research Education, entitled “Data Analysis Methods for Qualitative Research: Managing the Challenges of Coding, Interrater Reliability, and Thematic Analysis.”
“While … text books explain the general philosophies of the interpretive tradition and its theoretical groundings, I found few published studies where authors actually explained the details pertaining to exactly how they arrived at their findings,” says Mr. Belotto. In the article he shares the sources of information that he has found and the methods that he has used to address these challenges. He also discuss issues of trustworthiness and how matters of objectivity and reliability can be addressed within the naturalistic paradigm.
This is a must-read for anyone interested in the details of qualitative research and analysis.
Career Series: Mid-Career
Career Transitions: Becoming a Clinical Research Nurse
This is part two of a three-part series on research careers.
By mid-career, nurses are sometimes looking for new challenges. However, not all nurses are interested in pursuing careers in administration. One path to consider is in clinical research.
Nurses play an essential role in the success of clinical research. Although a principal investigator (PI) has ultimate responsibility for any clinical research study, it is often a nurse who does a significant amount of the coordination and execution of the study. From recruiting and screening participants to collecting data, a nurse can play a pivotal role in human subject protection and compliance.
There are a number of ways that a nurse can become involved in research. A staff nurse may encounter an inpatient or outpatient who happens to be enrolled in a clinical study. At hospitals that are striving for or maintaining their Magnet status from the American Nurses’ Credentialing Center, nurses may be involved in research directly. At academic medical centers, where advanced nurse practitioners work closely with clinicians who are also investigators on research studies. Nurses can also serve as investigators or sub-investigators on research studies.
Such is the case with Radica Palmer, RN, a nurse practitioner at Northwell Health. Her role as a clinic nurse has evolved over the years, and has excelled in a leadership role in research for her department. Ms. Palmer’s experience brings a unique perspective to the research programs in which she is involved.
“Having clinical knowledge offers a great advantage to the PI,” says Ms. Palmer. “The nurse can gather valuable information from patients and share it with the investigator, who can then make important clinical decisions.” Working closely with and mentoring study coordinators, a research nurse is a valuable asset to the clinical research team. A research nurse is also able to develop relationships with patients, which opens up communication and is beneficial to the study as well as the patients.
The relationship that nurses cultivate with patients or study participants is extremely important. Participants may feel more comfortable speaking to a nurse, and this can lead to their providing more details about their health or involvement in the trial. These nuances can have a material impact on the trial and might not always come up during a clinical visit with the physician.
For nurses who are interested in advancing their career into research, there are a few requirements that will prepare them to play this role. Understanding the clinical trial process is essential. First, he or she should take courses in Human Subjects Research (HSR) and Good Clinical Practice (GCP). Depending on their interest, nurses may also explore courses in institutional review board administration, compliance or regulatory topics.
As clinical trials increase in complexity, nurses who are interested in expanding their careers have many opportunities to further their careers in research. Nurses who are interested in exploring a career in research can consider some of these online courses:
Human Subject Research
HSR provides foundational training in human subjects research and includes the historical development of human subject protections, ethical issues, and current regulatory and guidance information.
Good Clinical Practice
GCP consists of basic and refresher courses that provide essential good clinical practice training for research teams involved in clinical trials of drugs, biologics, and devices.
Clinical Research Coordinator
This course focuses on the operational and regulatory elements needed for the ethical conduct of clinical research.
Career Series: Early Career
How to Attract and Keep the Best Research Coordinators
This is part of a series on career development for research professionals.
One of the most challenging responsibilities for an investigator is the recruitment and retention of talented staff, particularly research coordinators. Nationwide, there is a high turnover rate among research coordinators. This disruption in staffing can lead to delays in conducting research, from missing deadlines to entire studies being stalled.
Investigators recruit research coordinators from a variety of sources. Sometimes the role of study coordinator is viewed as an entry-level position, and those individuals hired to fill the role can be new to the workforce, and may have little experience. Many may be so-called Millennials, recently out of college.
Millennials, generally speaking, were born between 1980 and 2000. They are considered one of the most educated generations of our times. Their numbers are huge, surpassing those of the baby boomers. Much has been studied and written about their attitudes toward work and career growth.
Millennials in the workplace can be dedicated and creative, and eager to make a significant contribution to your research site. To retain this young talent and minimize the risk of study disruption due to turnover consider the following tips:
Respect the balance between work and personal life.
Unlike Baby Boomers, younger workers tend to integrate their work and personal life in a more fluid way. They prefer not to have a distinct separation between the typical eight-hour work day and their personal interests. That said, they tend to be more protective of their personal time.
Practically speaking, this means they prefer more flexibility in their work day. They may be willing to work later in the day, or evenings, as long as they can take some time during the day to run errands or do other things.
Provide opportunities for learning and professional development.
Millennial workers are easily bored and need to feel they are growing and expanding their knowledge. Invest in their professional growth by offering access to online courses — either focused on research or on specific skills. This will keep them engaged.
Think beyond salary.
While millennial workers understand the important of earning an income, a high salary is not the primary driver for work place happiness. Beyond a salary, consider offering flexible work hours, additional days off, or opportunities for telecommuting.
Avoid isolating millennial workers.
The work of a research coordinator can be solitary, with them working independently from others in the office. It requires a fair amount of entrepreneurship and independence. However, Millennials are usually motivated by dynamic, cross-functional positions. They also seek jobs that allow them to be in contact with and learn from interesting people, interacting with other professionals and teams.
If your millennial research coordinator reports directly to you, it is important to honor your time together to discuss projects or studies. Ensure they can participate in office meetings so they can gain an appreciation for how their work might be connected to other activities in the office.
Provide a constant feedback loop.
For Baby Boomers, performance feedback had traditionally formal review process tied to promotion and compensations, conducted at specific times. For Millennials, feedback is informal and is expected throughout the work week.
Give them a sense of purpose.
Millennials are inspired by a vision or purpose, not by a list of tasks. Millennials, in general, will not be content to simply complete forms and file documents. They are looking for meaning in their work. Remind them of the importance of their work in human subject protection. Keep them in the loop about the value of clinical research at your research site — the impact on medical knowledge in general and on patients specifically.
Leverage their knowledge of social networks.
The world of Facebook, Twitter, Instagram and Snapchat is a daily part of their lives. They will not react well to feeling disconnected, even at work. In fact, research shows that over half of Millennials would turn down a job that denies them access to social networks.
Their adept use of social network sites can help gain insights that may help you improve your study participant recruitment, as well.
In general, they key driver for Millennial job satisfaction is a sense of connection and purpose. A lack of connectivity makes them feel isolated, and they are likely to move on to other opportunities. A fully engaged Millennial research coordinator can, however, be a dynamic part of your research team.