Clinical Researcher™

The Authority in Ethical, Responsible Clinical Research

April 2018

Volume 32, Issue 4

All contents © 2018 ACRP. All Rights Reserved Clinical Researcher—April 2018 (Volume 32, Issue 4)

EXECUTIVE DIRECTOR’S MESSAGE

Bringing the Team Together

Jim Kremidas

[DOI: 10.14524/CR-18-4025]

With our ACRP 2018 annual meeting just 10 days away (as of the posting of this issue of Clinical Researcher), it’s an appropriate time to reflect on how we can all work together toward our common goal: providing the highest possible quality in the delivery of clinical trials. We’re all an integral part of a team effort full of dedicated professionals. Working together, we learn from each other. Learning together, we thrive.

ACRP’s conference is an excellent opportunity for thought leaders to huddle together to share best practices. To build on what’s working and learn from what isn’t.

You and your organization have some ambitious goals. We’ve been working with others in the industry to advance the professionalization of the clinical trial workforce by developing real- world standards based on the competencies required to be an outstanding researcher.

We’re also working to spotlight some of the highest performers in our industry. That’s one of the many reasons we’re excited about working with The Avoca Group to jointly recognize leading sponsors and contract research organizations (CROs) at the ACRP/Avoca Awards & Recognition Ceremony on Friday, April 27, during our annual meeting.

Finalists for the ACRP/Avoca Quality Awards were chosen by investigational sites through a research study conducted in conjunction with The Avoca Group over an eight-week period in early 2018. Investigational sites were asked to rate sponsor and CRO attributes (including responsiveness to questions, knowledge of the study protocol, and frequency of clinical research associate turnover, among others) and study execution (including setting of realistic patient recruitment goals, design of case report forms, and ease of electronic data capture systems, etc.).

We hope this award will serve as another way to highlight some of the best and brightest in our industry. We should celebrate as we learn from first-in-class operations!

On another note, it’s vitally important for us as an industry to find new ways to work closely with clinicians in the healthcare delivery marketplace. We have a tremendous opportunity to complement each other’s work in our communities at the local level.

Clinical trials are a vital catalyst for healthcare innovation. It’s time for clinical practitioners and clinical research professionals to redouble efforts to educate potential patients on the benefits of trials as another valuable tool in a patient’s broader health regimen.

I look forward to seeing you at the conference.

Jim Kremidas ([email protected]) is Executive Director of ACRP.

Clinical Researcher—April 2018 (Volume 32, Issue 4)

CHAIR’S MESSAGE

Spring into ACRP 2018

Kathryn Kimmel, CCRC, CCRA, ACRP-CP, FACRP

[DOI: 10.14524/CR-18-4023]

Spring greetings! As we enter a new season and look forward to an awakening of the Earth here in North America, my thoughts turn to our ACRP 2018 annual meeting, which runs April 27–30 at the Gaylord National Resort & Convention Center just outside Washington, D.C., in National Harbor, Md. I always find that my passion for research is renewed each year I attend the annual meeting, and it is so appropriate that it coincides with the beginning of spring.

The volunteers on our Content Advisory Board have worked tirelessly with the ACRP staff to bring to our members an exciting program this year. Since the meeting will be in the D.C. area, we are expecting a significant presence of visitors from the U.S. Food and Drug Administration, National Institutes of Health, and other local and regional governmental and nongovernmental organizations with ties to healthcare and human subjects research.

This is also an exciting year because of our first-ever collaboration with the Avoca Quality Consortium to hold the all-day 2018 Quality Congress (not included in the price of Full Conference registration) on Friday, April 27. We also have an exemplary lineup of vendors in the Expo Hall that should interest all attendees. We hope everyone will be able to join us during the Expo Opening Celebration in the Expo Hall on Friday evening, to be followed by an ACRP/Avoca Awards & Recognition Ceremony (the ceremony is included in the Quality Congress’s $599 price or for $100 separately).

In addition to the regular educational sessions and networking events on tap in the Full Conference schedule Saturday through Monday, don’t forget that a variety of Friday half-day and full-day workshops may be purchased individually when you register, whether or not you will be in town for the rest of the meeting.

As always, I look forward to seeing my many research friends and colleagues during the meeting, as well as to making new friends. If you have not already registered to attend this year’s event, there is still time to make arrangements. I promise you will find it informative and rewarding.

Kathryn Kimmel, CCRC, CCRA, ACRP-CP, FACRP, ([email protected]) is a Senior Clinical Research Associate with PRA Health Sciences and the 2018 Association Board of Trustees Chair for ACRP.

Clinical Researcher—April 2018 (Volume 32, Issue 4)

MANAGING EDITOR’S MESSAGE

The ABCs of IRBs and AMCs

Gary W. Cramer

[DOI: 10.14524/CR-18-4024]

If letters are the building blocks of the alphabet, then acronyms are surely the building blocks of clinical research. Where would we be without our CRCs, CRAs, and PIs dealing with CROs and handling EDC as they work on ePROs, eCOAs, CTMSs, eTMFs, and so on following the expectations of FDA, NIH, OHRP, EMA, ICH, and the HRPP in order to file INDs, IDEs, NDAs, and on and on and on? Whew.

In this issue, we turn our attention to the contributions made by professionals behind two of the clinical research enterprise’s bedrock acronyms—the folks in IRBs and AMCs.

Brand new to the field? Then I’ll spell it out that we are dealing here with institutional review boards (also known as ethics committees) and academic medical centers. We’re happy to feature a variety of talented contributors who have brought their unique perspectives to bear on some of the opportunities, challenges, and rationales behind how and why well-functioning IRBs and AMCs are critical to clinical research.

Meanwhile, speaking of acronyms that are associated with this issue’s theme, did you know that…:

• If you want to become a Certified IRB Professional (CIP®) or Certified Professional Institutional Animal Care and Use Committee (IACUC) Administrator (CPIA®), you should learn more about the PRIM&R (Public Responsibility in Medicine and Research) organization. • If you want to demonstrate your organization’s commitment to ethical research with volunteers, you should learn more about the AAHRPP (Association for the Accreditation of Human Research Protection Programs) organization. • If you want to connect your AMC with institutions having similar missions, you should learn more about the AAHC (Association of Academic Health Centers). • ACRP members who have questions to ask and/or insights and resources to share about IRBs, AMCs, or any other acronym under the clinical research sun can do so through the ACRP Interest Groups and ACRP Online Community.

That’s enough for now, IMHO. TCOY, everybody.

Gary W. Cramer ([email protected]) is Managing Editor for ACRP.

Clinical Researcher—April 2018 (Volume 32, Issue 4)

PEER REVIEWED

Study Start-Up Obstacles at an Academic Medical Center and How to Overcome Them

Julie Agriesti, CCRC; Paula Smailes, RN, MSN, CCRC, CCRP

[DOI: 10.14524/CR-17-0026]

Few clinical trials are lucky enough to experience no start-up obstacles at an academic medical center (AMC). More often than not, these sites have a multitude of issues to overcome getting a study off the ground; however, sponsors are paying more attention to how long it takes sites to navigate the process from site feasibility and qualification to budget/contract execution and first patient enrolled.

Site staff must take note of what kinds of obstacles they face. Knowing how these obstacles can be addressed and their associated processes improved will put sites in a position of being more appealing to sponsors when they are recruiting potential sites for new studies. For this reason, it is advantageous for site leaders to be proactive on what may be an issue at start-up, in an effort to streamline the process for future studies.

Feasibility

It is common for sponsors to send out feasibility questionnaires to determine if various sites might be qualified to conduct one of their studies. These assessments may elicit data from a site, such as metrics of their patient population or whether or not sites have the designated staffing or equipment.

When it comes to site data, it may be challenging to get patient metrics in the time allotted to return the feasibility form. In an effort to be proactive, site staff should get updates on patient population metrics on a quarterly basis, so that the information is easily accessible when feasibility questionnaires arrive. Sites may also develop a website or brochure with this information to be easily accessible to sponsors.

The bottom line is to make your site look ready and marketable for the next study.

Checklists for Quality

Once a feasibility questionnaire has been received, a study start-up checklist may be created in the eventuality the site is accepted for the study (see Table 1); this can help to keep the start-up process on track. A checklist would need to be adapted to the events in site start-up and serve as a guide to ensure all documents have been appropriately processed, equipment and supplies received, contract negotiated, and training completed.

Checklists may also need some adaptation based on site workflows, and can be used as a quality instrument in clinical research. In fact, healthcare safety activists have looked to checklists to solve a plethora of problems with their well-known utilization in the aviation industry.{1} Checklist compliance is increasingly utilized in healthcare organizations to improve quality, which can be translated to clinical research study start-up.

Site staff can construct their checklist to decide which start-up activities may be done in sequence and which items can be done simultaneously. Utilizing checklists at the beginning of the study is a means to keep staff on target with what remains outstanding and delaying study start.

Recruitment Plan

A common problem in clinical research trials is difficulty enrolling patients. In fact, in an average clinical trial, 20% percent of principal investigators (PIs) fail to enroll any patients and 30% enroll more slowly than expected.{2} This is a very real obstacle that needs to be considered when starting a new trial.

A careful review of the eligibility criteria is necessary to determine if the site has access to the size and/or kind of patient population necessary to support the study. Eligibility criteria should be realistic for the disease under study, and broad enough to allow enrollment of a sufficient number of subjects.{3} If the criteria are stringent, site staff may be challenged to recruit and retain the contracted number of subjects.

As the old saying goes, “Those who fail to plan, plan to fail.” The recruitment plan should be finalized prior to the initial institutional review board (IRB) submission. This is why it is essential to have a well thought-out recruitment plan at study start-up, because implementation of any outreach method added after approval will be delayed until IRB review.

If achieving success cannot be accomplished from recruitment exclusively through the site’s existing patient population, community outreach may be a necessary form of recruitment. This is especially true if the intervention is a novel therapy. For sites that are parts of large organizations or research networks, utilizing electronic medical records and data mining may be useful in finding the select population.

If there are concerns with study eligibility and recruitment prior to study start, be sure to engage the monitor or study sponsor. Concerns and foreseen issues may not be unique to your site, but the reality across many sites.

If enough sites bring up potential difficulties, the sponsor may consider amending the criteria to make it easier for recruitment goals. For this reason, it is not just beneficial to your site to raise concerns, it may also be advantageous for the overall success of the study. The recruitment plan will need to be completed before IRB submission, so attention to this step should begin when considering feasibility and completed as soon as the site has been notified of acceptance.

Regulatory Affairs

Regulatory affairs is another area that can be fraught with long wait times. Once the site has the IRB submission ready, it may sit in a long queue of studies waiting to be reviewed.

In the earliest stages of site feasibility, sponsors want to know how long it will take for IRB approval, and benchmarking may be used to compare the time frame to other sites. IRB approval times may vary based on whether the site uses a local or central IRB, or a combination of both.

Unpredictable timelines for institutional IRB and ethics committee deliberations may create significant delays for study start-up, and some organizations reported more efficiency and speed with the use of central IRBs.{4} This reality becomes clear when the time frames of local IRBs and the size of the institution are factored into the equation. For example, the large number of clinical trials being reviewed at AMCs may delay timely protocol review and explain why approval takes longer at these institutions.

Overcoming the long wait times from submission to approval can be difficult goal to achieve. The solutions for site staff include ensuring documents are complete in the initial IRB application and proactively address any key issues the IRB may identify. Having a contact at the IRB may help speed along the submission and provide updates on its progress, which can be relayed to the sponsor. For more active sites, it may be cost effective to have a full- or part-time regulatory specialist to handle this aspect of study management.

Budgets and Contracts

The budget and contract are usually the first must-handle start-up items the site will encounter after being chosen, but the amount of time it takes for them to be fully executed can be onerous. Many reasons account for this, but one of the biggest comes from complex budget negotiation strategies and practices that are understood by few—and mastered by even fewer—research professionals.{5}

Before a site can begin to negotiate, an internal cost calculation needs to be completed. Depending on the complexity of the study, requesting rates for different services may be a time- consuming venture. Add to it, the back-and-forth nature of the process, and several weeks can go by.

Further, in some instances, the financial staff may have limited experience with budgets and negotiation. To overcome this obstacle, it is crucial to be prepared; study success or failure can rest on this.{5} Preparing means knowing the protocol and required procedures, understanding the cost of running the study, and identifying problem areas. This can help make sure the process runs in a smooth and timely manner.

Data Management—What’s the Plan?

Out of the many obstacles that can delay study start-up, data management can often be overlooked since the IRB, budget, and contract usually take precedence. That could be a mistake, because the site could end up having multiple issues in relation to the electronic data capture (EDC) system that could prolong study initiation.

Site staff should check the sponsor’s EDC system requirements against capabilities at the site as soon as the information is available. Potential problems can include not having the right system requirements for the EDC system, not being able to submit data through tight firewalls, and not having fast enough Internet speed. Resolution of these issues may require support from the information technology department to upgrade web browsers or operating systems.

In addition, using EDC requires study personnel to have access to the system. Before that access can be granted, the study staff need to undergo training. Sites can inquire about training and access requirements for the EDC system, in order to alert personnel to the amount of time it will take to complete training; this may take several hours per individual, and any delays in having all of the necessary staff trained may impact access for everyone. Weekly reminders may be helpful to keep staff on task and avoid training procrastination.

Research Billing

It is important to consider billable items for research and establishing the appropriate research billing accounts before the study begins. The logistics will take time to establish; first up, a coverage analysis should be done to identify charges that may be covered by third-party payors, including Medicare. This may help to inform the study budget and may be considered with that process, too, in order to ensure compliant processing.

The goal is to correctly bill study items to the study and items covered by insurance to the patient. The necessity of this lies in the avoidance of fraud. Timeliness in the reconciliation of study and patient accounts when the study is ongoing will further support billing compliance.

Unfortunately, there are documented cases of sites that have not been successful at this process. Emory University agreed to a $1.5 million settlement for falsely billing Medicare and Medicaid for clinical trial services that were not permitted by the Medicare and Medicaid rules in a whistleblower case, while what is now known as USC Norris Comprehensive Cancer Center settled for $1.9 million after admitting to overbilling with oncology trials.{6}

Knowing your contract well at the start of the study can be a proactive measure that avoids downstream effects of study billing errors. It is typical for billing accounts to be established once the study is IRB approved, making this one of the final steps in the study start-up process.

Conclusion

Conducting clinical trials is a test of one’s skills in project management and the associated logistics that come with it. To get a study off the ground, many tasks need to be performed in order to maintain regulatory compliance and contractual obligations.

Knowing what the obstacles may be is the first step to devising a plan to overcome them. The second step is organization through the creation of a checklist to improve site quality by tracking completion of start-up tasks. Furthermore, centralized versus decentralized organizations may have additional variables that may further impact the flow of study start-up.

The ultimate goal is to eliminate the tendency to be reactive when things go wrong, and instead capitalize on proactive measures that lead to beautiful beginnings.

References

1. Clay-Williams R, Colligan L. 2015. Back to basics: checklists in aviation and healthcare. BMJ Quality Safety 24(7). http://qualitysafety.bmj.com/content/24/7/428 2. Youngquist L. 2012. Site driven metrics. Appl Clin Trials 21(3). www.appliedclinicaltrialsonline.com/site-driven-metrics?pageID=2 3. Liu MB, Davis K. 2010. A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons from a Horse Named Jim (2nd ed.). West Sussex, UK: Wiley- Blackwell. 4. Lamberti MJ, Chakravarthy R, Getz KA. 2016. New benchmarks for trial initiation activities. Appl Clin Trials 25(12). www.appliedclinicaltrialsonline.com/new- benchmarks-trial-initiation-activities 5. Parke J. 2013. Negotiating effective clinical trial agreements and study budgets with research sites. Appl Clin Trials 22(4). www.appliedclinicaltrialsonline.com/negotiating- effective-clinical-trial-agreements-and-study-budgets-research- sites?id=&sk=&date=&pageID=2 6. Association of Clinical Research Professionals. 2016. Clinical trial billing errors generate multi-million dollar fines. ACRP Blog. https://www.acrpnet.org/2016/03/04/clinical-trial- billing-errors-generate-multi-million-dollar-fines/

Julie Agriesti, CCRC, ([email protected]) is a research site manager at The Ohio State University Wexner Medical Center.

Paula Smailes, RN, MSN, CCRC, CCRP, ([email protected]) is a member of the ACRP Editorial Advisory Board, a senior training and optimization analyst for clinical research at The Ohio State University Wexner Medical Center, and a visiting professor with Chamberlain College of Nursing.

Table 1: Study Start-Up Checklist

DATE

TASK COMPLETED PERFORMED COMMENTS Confidential Disclosure Agreement signed by PI and submitted Feasibility confirmed by team and submitted Notice of sponsor selection received Notify organization of new study, if applicable: Request contract and budget Receipt of regulatory packet or access to investigator portal online Recruitment plan developed Informed consent form versions approved by sponsor Prepare IRB submission packet:

 Site patient recruitment letter

 Site Web advertisement

 Questionnaires

 Radio ad script

 Sponsor’s attachments

 Phone script  All print ads

 Public service announcements

Protocol

Investigator brochures and package inserts Protocol submitted to IRB Regulatory packet to sponsor:

 1572-2 signed originals

 CVs and medical licenses

 Financial disclosures

 Protocol signature page

 Site responsibilities logs

 Lab certifications and ranges Establish accounts with Research Billing Office Internal budget finalized for sponsor IRB approval received and sent to sponsor Sponsor site initiation visit set up Medicare analysis form submitted and lab accounts established Sponsor’s training completed Regulatory binders received Study drug received Study supplies received If laptops, ECG machines, or other pieces of equipment are provided by the sponsor, these need to be checked by clinical engineering Dry ice agreements Site initiation complete Recruitment plan enacted

Clinical Researcher—April 2018 (Volume 32, Issue 4)

PEER REVIEWED

An IRB Perspective on Improving Informed Consent

Julie Blasingim, MBA, CIP; Sandra “SAM” Sather, MS, BSN, RN, CCRC, CCRA

[DOI: 10.14524/CR-18-0003]

The informed consent process is essential to the ethical conduct of research on new medicinal products, therapies, and approaches to improving healthcare. The investigator can use various tools to optimize this process, but the most important feature of informed consent is the investigator’s commitment to high standards in its conduct. This article looks at the institutional review board’s (IRB’s) perspective on the informed consent process, and how electronic informed consent is propelling human research forward.

Background

Technology continues to transform how society receives and retains information. With more people using electronic devices to read and retain information, it is the logical step to do the same for obtaining informed consent in clinical research. Electronic consent (eConsent) solutions can serve as a tool for investigators for obtaining and documenting informed consent, and can help address many of the challenges associated with the traditional, paper-based consent process. Solutions can come in the context of a variety of media, including text, audio, and video features woven together to create a multi-dynamic approach to enhancing subject comprehension. The introduction of eConsent represents a major advancement in comprehension, experiences, and overall clinical research program improvement.

A credit to its many benefits, the interest in eConsent continues to grow, and it is increasingly being adopted by sponsor and contract research organization (CRO) study teams and research institutions. A recent survey capturing the opinions of 146 respondents from 100 biotech, pharmaceutical, CRO, and IRB organizations revealed that the major factors driving eConsent adoption today are the opportunities brought by enhancing understanding and improving overall participant satisfaction.{1} Indeed, the momentum of adoption is likely to continue, with 55% of respondents saying that their organizations will adopt eConsent over the next 12 months, rising to 82% by 2020.{1}

There are many stakeholders involved in implementing an eConsent solution, and this article will provide thoughts from an IRB perspective, including traditional consent vs. eConsent, benefits and opportunities, challenges and barriers, preparation and best practices, and the importance of collaboration among stakeholders.

The Current Consent Process

Informed consent is a requirement set forth by a number of U.S. regulatory authorities, such as the Food and Drug Administration (FDA) through the Federal Policy for the Protection of Human Subjects in Research (the Common Rule), and it is incorporated in international guidelines for conducting human research, including those from the International Council for Harmonization (ICH).

FDA mandates in 21 CFR Part 50.20 of the Code of Federal Regulations, “No investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.”

Often people mistakenly view the term “informed consent” to mean simply obtaining a handwritten signature on a lengthy consent document. The process of informed consent starts when the study begins recruiting participants, and it continues providing the potential participant with adequate information so that he or she can make an informed decision on whether to participate in the research. Potential participants must be allowed ample time to read the consent form, discuss the study with the site study personnel and their friends and family, and ask the study team questions. In addition, the process is an ongoing decision for participants, and they need to decide not only in the beginning, but also throughout their time in the study, if they want to continue their participation when new information arises.

FDA regulations require that an IRB/ethics committee review and have the authority to approve, require revision or modification, or disapprove a study. Sponsors and investigators considering an eConsent solution must obtain IRB/ethics committee approval of the consent document text, technology platform, and embedded media.

Traditional, paper-based informed consent has evolved to be a lengthy document that often includes complex and confusing information for participants, incorporating legal jargon that is of little value to someone trying to make an informed decision as to whether to participate in the research. From an IRB review perspective, a document this complex could be overwhelming for potential participants. As a result, the IRB must evaluate the process in which paper-based informed consent is used, to ensure that there is ample time for the participant to comprehend the information. Further, IRBs often query what measures are in place to assess comprehension, how researchers will answer participant questions, and whether the participant has the option to take the paper-based informed consent home to discuss with others.

A paper-based informed consent is limited to static text, pictures, and diagrams (unlike eConsent, which can include multiple forms of media that may not only provide information in a dynamic way, but include additional resources and information by using links to Internet material [e.g., dictionary]). Version control can also be challenging with traditional informed consent, with sponsor and IRB versions as well as subsequent, site-specific versions.

Changes to a paper informed consent can be slow to disseminate. These changes need to be made across hundreds of sites for a single study, and with a paper-based system, this can take a significant amount of time and logistics, thereby introducing an element of risk. Compliance issues could potentially arise if a site is using an outdated version of the consent because site staff have not yet received the updated approved documents or unintentionally used an outdated or draft version.

Traditional Consent and eConsent: The Differences

No matter the format for the informed consent process—paper, eConsent, or a combination—the responsibilities set forth in the regulations related to the IRB and investigator have not changed; how they are accomplished changes, and some of those in an eConsent environment are performed by the eSystem. The traditional, paper-based process is recognized as having limitations in effectively supporting the IRB and investigator. With so many eConsent options available, it is important to think about each study individually, and how eConsent will impact the informed consent process on a case by case basis.

There are certain elements of consent, from an IRB review and a regulatory perspective, that must be included in any consent, regardless of the format. The following elements are particularly crucial when discussing eConsent:

• A signature is required from either the subject or his/her legally authorized representative, unless a waiver of documentation has been approved by the IRB. • The process must facilitate comprehension, including the investigator or designee answering the subject’s questions prior to signing. • Language must be understandable and not include exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights.

An IRB’s review of eConsent is essentially focused on protecting the human subject and ensuring that each participant is offered a comprehensive and informative consent process. This includes assessing how eConsent can contribute to better protection for individuals participating in research.

What is different?

• The Interface. eConsent is more interactive, and can include text, graphics, audiovisual, animation, website links, and more, which can also result in more information being available to participants. • Subject Comprehension. eConsent has the potential to help improve subject comprehension by providing hyperlinks to more detailed information about a particular subject area. • Timely Adjustments. Depending on the vendor, eConsent allows for version control by only providing the latest approved version to the site to use, and for more timely amendments to implementation/subject notification. • Improved Oversight. Greater sponsor and CRO oversight of the study, resulting from greater access to timely data collected during the informed consent process. • Subject Familiarity. Many people prefer to view information electronically because they use similar devices in their everyday lives.

Opportunities with eConsent

Most IRBs are aware of the issues with paper-based informed consent and embrace eConsent for its significant enhancements to the consent process. eConsent offers many opportunities to improve subject enrollment and retention and the ability for researchers to oversee these. There is also the opportunity to present information better, with better assessment of an individual’s comprehension that can be built right into the system. For example, in eConsent, the flow of information can be adapted so that it is not a linear page of words.

Having the ability for someone to take a break, track their progress, and/or ask questions as they go along results in better-informed participants who are making an informed decision when they commit to being in the study (and they understand what their compliance requirements are). Better-informed participants are more likely to stay on a trial and be more committed.

However, 44% of people asked in recent research said that concerns over gaining IRB approval of eConsent was a barrier to implementation.{2} In the U.S., there is a lot of acceptance of eConsent, especially when working closely with an IRB upfront, before study review. From an IRB perspective, benefits include:

• Better Subject Comprehension. Having an interactive interface, such as the audio/visual effects and hyperlinks that are typically included within eConsent, may help facilitate not only the subject’s understanding of the information presented, but also his/her ability to retain the information. • Transparency, Auditability, and Control. eConsent solutions can track how long individuals are on any given page, if participants skipped a page or skipped something that may be of value, and pages where they flagged questions. Many systems include a way for subjects to highlight text that they may not understand in order to discuss it with the investigator, and many have a way to “test” the subjects’ understanding of the information, whether it be at the end of the consent process or anytime throughout. • Integration. eConsent can be integrated or tracked into other eSystems. • Informed Consent Form (ICF) Version Control. Version control is tightly tracked and managed by most platforms, and there is a much quicker way to close past versions of the consent and disseminate new updated consents to participating sites. o From an IRB perspective, there is also the ability to quickly stop individual sites from accessing ICFs if there are any noncompliance issues or unanticipated problems, or to verify that a site is using the correct version for more critical and timely reconsenting needs. • Faster Processes. Integration and dissemination of new information (e.g., risks, additional procedures, etc.) can be handled much faster in an eConsent solution. • Timeliness. Working with an IRB upfront promotes timely entry of eConsent data into the study databases and allows for more timely collection of the subjects’ informed consent from remote locations.

However, the adoption of an eSystem to support consent brings some risk and the need for sites, sponsors, and IRBs to determine the impact on their consent processes. The challenges and barriers to adopting eConsent at many sites come from the lack of experience with eConsent to support the better understanding of the following: • Cost/return on investment • Change management for the site, sponsor, and IRB study team adoption into current quality systems • For consent development, the ability for ICF content contributors to easily edit and communicate changes needed • Participant adoption/comfort • Perceived IRB acceptance of the multimedia format • IRB oversight (will IRBs have access to the system tracking?) • Impact on compliance • Variability in regulatory requirements for eSystems • Consistency in approach from vendors related to what part of the consent process is documented by the system, within the system, or outside the system (e.g., site discussion with the participant about his or her study questions)

Sponsors, CROs, sites, and eConsent vendors typically describe the above as barriers or typical management challenges associated with implementing a new technology in an area that is highly regulated and has a high personal touch to it. The above challenges can be grouped into four areas: 1) the impact to the study team’s informed consent quality systems, 2) the cost or return on investment, 3) adoption—will the people participating in the studies be comfortable with it, and 4) the regulatory/IRB considerations—will the solution meet all the requirements.

Gaining Approval

For the IRB, reviewing an eConsent is quite different from reviewing a paper-based consent. Unlike with electronic participant-reported outcome (ePRO) systems, where the IRB only approves the content, the IRB reviews both the eConsent content and the eConsent platform. This means reviewing just a Word document of eConsent content or screenshots is not sufficient—the IRB needs to also review the content in the same context as a participant will review it, so reviewers need to see the complete eConsent system, including any hyperlinked or interactive portions. Beyond the elements of consent, the IRB looks for aspects such as ease of navigation, identity verification, remote consenting as an option, system security, and additional comprehension measures or features that are only available because the consent is electronic. To gain approval, the following must be considered:

• All elements of consent must be included • Adequate study information • Process—place, method, acceptable time of Q&A • That process facilitates a subject’s or potential subject’s comprehension • Documentation of informed consent • Language understandable to participants • Security of data collected and shared

The format is also different. Because every eConsent platform is different, IRBs need to have flexible review processes to accommodate the variety of review methods available. Developing a review process around one platform can create unnecessary submission requirements and may distract the IRB from important review elements. Different elements include paper, storyboards, graphics, hyperlinks, videos, and final formatted layouts.

The following should be completed upfront to facilitate speedy IRB approval:

• Encourage the IRB and eConsent vendor to collaborate. Collaboration is key with all stakeholders, including sponsors, ethics committees, vendors, research sites, etc. o Try to work with representatives from an IRB and vendor who are willing to collaborate—this is critical as early in the process as possible. o Choose an IRB that supports and has experience in e-collaboration. • In advance, the IRB receives information regarding: o Security features o Security access o Signature requirements o Change management o Principal investigator/site training • IRB pre-approves system for study and any future study with the vendor. • Vendor provides IRB with access to the eConsent system so that study-specific eConsents can be reviewed in the native environment.

Best Practices at Protocol and Site Levels

Advice for best practices at protocol level:

• Vendor works with sponsor to develop eConsent solution • IRB has direct access to the eConsent system • IRB reviews and edits as needed • Copies consent vendor who implements changes • Vendor sends IRB attestation document confirming the electronic version is equivalent to the IRB-approved, paper version • IRB copies vendor on amendment approvals; vendor quickly incorporates changes

At site level:

• IRB copies vendor on site submission/approval to add site specific language • Vendor incorporates site-specific items and sends IRB attestation and site specific eConsent • Amended eConsent solution is quickly disseminated and "outdated" versions are archived

Moving Forward

There have been many changes over the last few years regarding acceptance of eConsent and a greater shift toward its use. Ultimately, better-informed research participants are better research participants: they understand more, so they are more likely to stay on for the duration of the study. eConsent will likely continue to integrate into other subject notification systems for ongoing information about the study, including study results (i.e., lay summaries) and critical new information that needs to be immediately communicated to the participants.

It is easy to see the benefits of eConsent and support its usage—when implemented properly, eConsent makes some real improvements to the informed consent process, which is in everyone’s best interest. The logistics of using eConsent—and collaboration and communication between IRBs, study sponsors, researchers, and eConsent vendors—are critical concerns as stakeholders work toward an efficient and thorough review process. eConsent may take more time than the traditional, paper-based consent process, but it’s worthwhile.

References

1. Sather S. 2017. Surveying the state of eConsent: are there still barriers to be broken down? Appl Clin Trials. www.appliedclinicaltrialsonline.com/surveying-state-econsent- are-there-still-barriers-be-broken-down 2. CRF Health. 2017. Webinar recording presented by Sandra “SAM” Sather. Visibility and oversight: what paper informed consent isn’t offering you. http://resources.crfhealth.com/webinars/visibility-and-oversight-what-paper-informed- consent-isnt-offering-you

Julie Blasingim, MBA, CIP, (mailto:[email protected]) is Director of IRB Reviews at Advarra IRB.

Sandra “SAM” Sather, MS, BSN, RN, CCRC, CCRA, ([email protected]) is Vice President at Clinical Pathways, LLC and a Regulatory and Quality Consultant for TrialConsent at CRF Health.

Clinical Researcher—April 2018 (Volume 32, Issue 4)

PEER REVIEWED

Central IRB vs. Institutional IRB—Advantages and Disadvantages for Multicenter Trials

Pranali M. Wandile, MS, CCRP

[DOI: 10.14524/CR-17-0009]

U.S. Food and Drug Administration (FDA) guidance documents, particularly the cooperative research guidance given in 21 CFR 56.114 of the Code of Federal Regulations, only provide suggestions and recommendations. These recommendations do not have legal force. Still, the FDA urges sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved in multicenter clinical research to adhere to these guidelines and requirements as outlined in 21 CFR part 56.

These guidelines recommend the use of a centralized IRB review process in situations where doing so could improve the efficiency the review. In multicenter trials, however, review by both central and institutional IRBs can duplicate efforts, increase expenditures, delay clinical trials, and cause confusion and miscommunication. Meanwhile, undergoing only a centralized IRB review and foregoing the institutional IRB review can save time, reduce expenditures, reduce delays in subject enrollment, and decrease the workload and financial burden on an institution.

This article stresses that protecting the rights, safety, and welfare of study subjects is the most important element of clinical research, and that researchers can meet all of these goals by using either a central IRB or an institutional IRB, instead of using both. Observations from the Field

Taking part in the challenging development of a clinical research department in a brand new institution where the staff were unfamiliar with the fundamentals of clinical trials, the author found that administrators at the new facility wanted their studies to be review by a local IRB, but at the time, they only had an incomplete IRB standard application. We found critical pieces of information regarding the operation of institutional IRBs were missing, such as the requirements for establishing an IRB infrastructure, IRB functions, initiation of the IRB review process, etc. Nor were the administrators aware of the option for using a centralized IRB review process.

Looking at the hospital infrastructure and the resources our site had, we thought the centralized IRB review process would be the most suitable option for clinical trial oversight at our facility. After all, quality conduct of clinical trials is of utmost importance, and trials should not proceed without thorough IRB review.

We e-mailed the FDA questions regarding IRB determination for our new research site, and we were pleased to receive a prompt response to our questions. After conversations with the FDA, we were able to answer the new facility’s most puzzling questions. This experience prompted the development of this article to share the “lessons learned” from this experience.

Background

The FDA's guidance regarding the use of centralized IRB review processes in multicenter clinical trials assists sponsors, institutions, IRBs, and clinical investigators in meeting the requirements of 21 CFR part 56. While these requirements have no legal force, the recommendations do provide standards to which facilities should try to adhere.{1}

The guidelines allow facilities to use only the centralized IRB review process, especially when this centralized review could improve the efficiency of the IRB review. Multiple offices within the FDA established these guidelines, including the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the clinical practice program in the Office of the Commissioner, and the Office of Regulatory Affairs.{2} 21 CFR part 56 addresses the IRB review and approval process. These guidelines apply to clinical investigations that are subject to Investigational New Drug (IND) regulations, unless they are exempt from IRB requirements under part 56.104.

Responding to a history of significant abuses human study subjects have endured in various notable experiments, regulators developed procedures intended to ensure the safety of participants. These abuses led to the creation of the National Research Act of 1974 and the Belmont Report, which required researchers who use human subjects to adhere to critical ethical principles. The ethical principles include respect for persons, beneficence, and justice. An IRB may approve human research only in situations in which a) the potential benefits to society outweigh the risks to subjects, b) there is unbiased selection of study subjects, and c) equal distribution of risks and benefits to eligible participants is present.{3}

Principle Investigator and IRB Review Responsibility

The principal investigator (PI) bears ultimate responsibility for the complete oversight of the study, and for assuring compliance with IRB policies and procedures along with the locally applicable regulations and guidelines from competent authorities.

For studies conducted under the aforementioned IND application with the FDA, the sponsor of the IND must obtain assurance that the PI will meet the requirements outlined in 21 CFR part 56 pertaining to the IRB review and approval processes. In fact, sponsors initiate the process by submitting site information to the IRB, or by instructing the site to submit study and site information to a central IRB (the IRB suggested by sponsor) for review and approval.

In a multicenter trial, if the PI is conducting clinical research in an institution with its own local IRB, then he or she must follow the policies of that institution. However, the institutional policies can also state that the PI pursue review through a centralized IRB or through the institution's IRB, or through joint review responsibilities of both.{2}

The Requirements for IRB Membership

As per 21 CFR 56.107(a), an IRB member must have sufficient experience, expertise, and diversity to ensure adherence to the IRB’s advice and counsel in safeguarding the rights and welfare of human subjects.

Usually, sponsors utilize a central IRB to oversee a study. If an institution has its own IRB, then depending on the institutional policies, the institution may need to submit the study to its own IRB for study approval and oversight, it may opt to partially depend on a central IRB, or it may make the central IRB fully responsible for study oversight.{2}

Centralized IRB Review of Research Protocol

In multicenter trial cases of institutions that have their own institutional IRB nevertheless wishing to rely on a central IRB for partial or complete review of the study, the institutional IRB should sign an agreement with the central IRB. Copies of that agreement should be held by the institution, the investigator, and the central IRB.{4} There should be written procedures for both IRBs that address these questions:{2}

• How does the institution’s IRB determine that the central IRB is qualified to review research conducted at the institution? • How does the central IRB intend to communicate with investigators, relevant institutions, and with the institution’s IRB regarding its review? • How does the central IRB ensure that it provides meaningful consideration of relevant local factors for communities from which research subjects will be enlisted for the study? • How does each IRB share responsibilities under the agreement? • How does the central IRB measure the ability of a remote site to participate in a study (e.g., to make sure the site has medical services appropriate to the complexity of the study)? • How does the central IRB perform initial and continuing review responsibilities at remote sites?{2} In the case of the study being launched by the research-naïve institution mentioned earlier, the author and others at the institution found the experience of using only a central IRB was extremely positive. Staff were able to start the study within two months of the day the sponsor approached the institution with the new study proposal. While the contract department reviewed the contract and budget, a research coordinator submitted the study to the central IRB. By the time the contract and budget negotiations were finalized, the IRB had approved the research protocol.

In short, using the central IRB saved a remarkable amount of time, resources, and expenditures from the study start-up phase until its closure—time that was capitalized on by staff to focus on quality study conduct and oversight.

Benefits of Using a Central IRB

In a multicenter clinical trial, it can become a very costly and time-consuming scenario if each institution involved submits the research protocol to its own IRB as per the institutional IRB guidelines, possibly leading to major delays in the initiation of the study activities at all of the study sites. Generally, institutions have multiple studies going on at the same time, and using both an institutional IRB and a central IRB in every case unnecessarily duplicates efforts, increases expenditures, and delays clinical trial conduct.{5–7}

Utilizing the centralized IRB review process for multicenter trials can save time and expenditures, reduce further delays in enrollment, and reduce the workload of the institutional IRB. Thus, many institutions use their own local IRB specifically for internally funded, investigator-initiated clinical trials, but opt for central IRB services for externally funded clinical trials.

The FDA’s “Guidance for Industry Using a Centralized IRB Review Process in Multicenter Clinical Trials” mentions that the use of a centralized IRB review process is consistent with the requirements of existing IRB regulations. CFR 56.114 on Cooperative Research states that “institutions involved in multi-institutional studies may use joint review, or rely upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.”{8} In fact, a central IRB can be created for reviews of multicenter trials in specific therapeutic categories by members who are highly qualified in their medical specialties. For example, the National Cancer Institute (NCI) has a central IRB that reviews all NCI-sponsored adult oncology Phase III multicenter trials. Study sites conducting NCI trials can use the NCI’s central IRB, or they can use their own IRB for study oversight.{1}

Some multicenter trials involve multiple academic medical centers. In such cases, each single medical center can use its own IRB, or can accept study oversight from another participating medical center’s IRB. These two medical centers can sign the cooperative agreement accordingly.

One of the biggest advantages of using a uniform central IRB in a global multicenter trial is that the central IRB collects the clinical trial information from all of the active sites across the globe. If the central IRB review and oversight is efficient, then it will be able to detect safety problems quickly and easily, which will not only be helpful in further continuing the trial, but for all future pipeline studies for the same investigational product.

Issues with Utilizing a Central IRB

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research suggested that IRB members should include “men and women of diverse backgrounds with sufficient maturity, experience, and competence, so that the IRB will be able to do its responsibilities, and its determinations will be accorded respect by investigators and the community served by the institution or in which it is located.”{9} It is also suggested that the IRB members be able to determine whether the proposed research is acceptable in terms of standards of professional conduct and practice, institutional commitments, regulations, and applicable laws.

A central IRB can be located within an institution that is conducting a multi-institutional research study, and can provide oversight for different sponsors and across study sites not located in the same territory in which the IRB and its host institution are based. In such cases, the central IRB may not be fully knowledgeable about the details “on the ground” at the various sites. For example, site management organizations or hospitals may use a central IRB that is not located in the community in which an actual study is being conducted.

However, the central IRB still needs to review a variety of factors with an unbiased approach, including the attitudes of the communities where the research is being conducted, the ethical standards found locally,{10} and any pertinent local cultural influences on the population from which research subjects will be enrolled. Even members of a very experienced central IRB may not be aware of these nuances in all of a study’s settings.

Therefore, a centralized IRB review process should include the following provisions to ensure that these relevant local factors receive substantial consideration:

1) Individuals or organizations familiar with the local community of a study site should submit relevant local information to the central IRB. 2) The centralized IRB’s limited review of the study should be followed by the relevant institutional IRB’s limited review of the same study, focused on the issues of concern to the local community.{2}

According to 21 CFR 56.114, for the centralized IRB review process, “Institutions involved in multi-institutional studies may use joint review, or [may] rely upon review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.”

In the case of a joint review, confusion and miscommunication can occur, as not all of the study staff will be aware of the details of a local IRB’s agreement with a central IRB. In such cases, knowledge must be thoroughly disseminated to the study staff so that both IRBs can efficiently oversee the clinical trial.

Local IRB Review of Research Protocol

IRB regulations require that the IRB should be able to ascertain the acceptability of proposed research in terms of institutional commitments, regulations, applicable laws, standards, or professional conduct and practice. These requirements are applicable to both local and central IRBs. IRB review through members who have been carefully selected (based on their subject matter expertise and/or familiarity with the local community) is intended to provide meaningful consideration of a variety of factors in assessing research activities. These factors include unique local/state laws, local and institutional considerations, and cultural backgrounds of the population from which research subjects will be drawn (e.g., ethnicity, educational level, religious affiliations, vulnerable populations, inter-community differences, etc.). Additional matters that require assessments include whether mechanisms of subject selection will be equitable, whether adequate provisions are made to minimize risks to vulnerable populations, and whether the informed consent process is adequate.{2}

Local IRB records should contain the agreements and procedures that the IRB and its host institution are required to follow to conduct clinical trials (according to 21 CFR 56.115(a)), including guidelines regarding initial and continuing review of clinical trials, reporting of protocol events, reporting of clinical trial findings, and other actions expected on the parts of the investigator and the institution.

Benefits of Using Local IRB

• Local IRBs can review multiple types of studies onsite, such as internally and externally funded trials. • They can provide IRB services to other facilities and collaborating institutions as well. • They can lead to a better understanding of local customs, sensitivity of community attitudes and ethical concerns, and standards of care in the community where the research study will be conducted and from which research participants will be drawn. • The speed of the research protocol review is locally controlled. • The IRB members and the investigators become familiar with each other and with the utilization of common research techniques, which is helpful in quick review of future upcoming studies.{11}

Issues with Using Local IRB

• In the U.S., local IRBs must be registered with the Office for Human Research Protections within the U.S. Department of Health and Human Services, which requires Federalwide Assurance. • Start-up costs and annual expenditures of a local IRB can be considerable. The host institution pays the salaries of the IRB members and the staff associated with it. • Additional financial burdens can or will emerge, tied to such matters as a) the requirement of having expert IRB members representing the therapeutic/research areas of focus at the institution, b) increases over time in study workloads leading to a need for more staff to accomplish the IRB requirements, c) development and maintenance of written IRB policies and procedures, and d) obtaining substantial institutional/facility support. • The activities demanded of local IRBs can be time-consuming concerns, especially at institutions which are highly active research sites for both internally funded/investigator- initiated trials and externally funded trials.

Risks of Using Both Central and Local IRBs

Differences in what are considered approved research practices between multiple IRBs could affect the IRB review process and cause confusion for site staff. IRBs could interpret the same regulations differently as a whole, or interpretations among their individual members could differ. Therefore, in cases of complex protocols being reviewed, an IRB may want to apply higher (uniform) standards than those explained at a basic level in the federal regulations.{6}

For example, the expectations and criteria regarding staff reports of serious adverse events and protocol deviations could differ between local and central IRBs. As a result, some important events may not be reported. Research study staff are also burdened with multiple studies at one time; this could be an additional concern since the reporting criteria may differ between protocols as well as between IRBs.

The question arises, what are we going to achieve by using two IRBs for research study oversight? If the members of different IRBs are all qualified experts, it may be hoped that there is little to no variation in their opinions, assuming uniform regulatory standards are applied during the review process.

Monitoring is the most important and extensive part of clinical trials, as a study’s results rely on the accuracy of study data and the authenticity of clinical trial conduct. We do not duplicate the monitoring work, so why should we duplicate the IRB review process? Can we not achieve perfection without the redundancy? If not, then it would appear we need to duplicate every part of work in clinical trials, including coordinating, monitoring, PI review, FDA submission, etc.{6}

Benefits of Using Both Local and Central IRBs

Research study–related findings or violations that may go unnoticed in a review by one IRB may get caught by another IRB’s review, so having both a local and central IRB for study oversight can act as a double layer of protection for the study subjects and for ethical, quality conduct of clinical trials.

Conclusion

This article addressed various advantages and disadvantages of having central and institutional IRBs involved in the clinical trial process. The key responsibility of an IRB is to protect the rights, safety, and welfare of study subjects, which are essential matters in the clinical research process itself. We can achieve this goal by using either central or local IRBs, as long as the ethical practice of clinical trials are guaranteed and the autonomy and beneficence of study subjects are fully protected.

References

1. National Cancer Institute. 2016. Central Institutional Review Board—Standard Operating Procedures. https://www.ncicirb.org/sites/ncicirb/files/CIRB%20SOPs%20051716_v2.pdf

2. U.S. Department of Health and Human Services/Food and Drug Administration. Guidance for Industry—Using a Centralized IRB Review Process in Multicenter Clinical Trials. www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127013.pdf 3. Marsden S, Melander M. Historical Cases of Unethical Research. https://www.und.edu/instruct/wstevens/PROPOSALCLASS/MARSDEN&MELANDER2.htm

4. Federal Register (Vol. 46, p. 8966; January 27, 1981).

5. Burman W, Breese P, Weis S, Bock N, Bernardo J, Vernon A. 2003. The Effects of local review on informed consent documents; from a multicenter clinical trials consortium. Contr Clin Trials 24:245–55. https://www.ncbi.nlm.nih.gov/pubmed/?term=The+Effects+of+local+review+on+informed+cons ent+documents%3B+from+a+multicenter+clinical+trials+consortium

6. Silverman H, Hull SC, Sugarman J. 2001. Variability among institutional review boards' decisions within the context of a multicenter trial. Crit Care Med 29(2):235–41. https://www.ncbi.nlm.nih.gov/pubmed/?term=Variability+among+institutional+review+boards% 27+decisions+within+the+context+of+a+multicenter+trial

7. McWilliams R, Hoover-Fong J, Hamosh A, Beck S, Beaty T, Cutting G. 2003. Problematic variation in local institutional review of a multicenter genetic epidemiology study. J Am Med Assoc 290(3):360–1. https://www.ncbi.nlm.nih.gov/pubmed/12865377

8. Federal Register (Vol. 40, pp. 47688–700; August 14, 1979).

9. Federal Register (Vol. 44, p. 47699; August 14, 1979) and Federal Register (Vol. 43, p. 56174; November 30, 1978).

10. Federal Register (Vol. 46, pp. 8958–70; January 27, 1981).

11. Rice TW. 2008. How to do human-subject research if you do not have an institutional review board. Resp Care 53(10):1362–7. www.rcjournal.com/contents/10.08/10.08.1362.pdf

Pranali M. Wandile, MS, CCRP, ([email protected]) is Site Director for Central Valley Research, LLC in Fresno, Calif.

Clinical Researcher—April 2018 (Volume 32, Issue 4)

SPECIAL FEATURE

IRBs Play Waiting Game with Revised Common Rule Implementation

Matthew Harrington

[DOI: 10.14524/CR-18-4022]

Sometimes it pays to procrastinate.

Institutional review boards (IRBs) that put off the work needed to comply with the revised Common Rule got a reprieve in January when compliance was delayed by six months.1

Just two days before the new rule was to take effect, an interim final rule pushed the deadline to July 19, 2018. Formally known as the Federal Policy for the Protection of Human Subjects, the Common Rule provides direct oversight for new and ongoing research funded by the federal government. It only regulates federally funded research, unless an institution chooses to apply the rule to its other studies. The proposed revisions are intended to facilitate research and reduce the burden, delay, and ambiguity for investigators.2

The delay is having the opposite effect, creating headaches for those IRBs that refreshed their standard operating procedures (SOPs), consent forms, and databases, and took other measures to meet the updated Common Rule. That means for now their diligence in following the new standards will go unrecognized.

Institutions are Advised to Prepare for the 2018 Effective Date

“Let’s say you were ready,” says Ernie Prentice, Professor Emeritus with the University of Nebraska Medical Center (UNMC). “You revised SOPs, updated submission forms, and reconfigured databases to comply with the new Common Rule. But, because of the suddenly announced delay, now these forms and systems do not work.” IRBs are required to revert to the old Common Rule to accommodate new and ongoing research proposals.

“Ironically, institutions that did little to prepare for the new Common Rule might be better off,” says Prentice, the former Institutional Official for both the UNMC Animal Care and Use Program and the Human Research Protection Program. “It’s a bit of a mess, depending on how far institutions went to be ready to comply.”

The six-month delay is intended to give institutions and the federal government more time to prepare and provide guidance for the 2018 requirements.

It turns out, however, that the wait may not be over in July. Federal agencies are in the process of developing a new Notice of Proposed Rulemaking to further delay the required implementation (for example, until January 21, 2019). However, institutions are being advised to prepare for the July 19, 2018 effective and compliance date.3

Applying the Belmont Report to the Modern Research Enterprise

This round of waiting is par for the course. Revising the Common Rule has been a long and arduous process that officially started with an advanced notice of the proposed changes in 2011, though it had been under discussion for far longer. The goal of IRB review is to assure that the rights and welfare of participating research subjects will be adequately protected in the pursuit of a proposed research study.4 The Common Rule itself has roots in protections first published four decades ago.

In 1991, the U.S. Department of Health and Human Services (HHS) began a process leading to the adoption of regulations by 15 federal departments and agencies. As a result, subpart A of 45 CFR part 46 in the Code of Federal Regulations became known as the “Common Rule,” which has not been amended since 2005.

Since then, shifts in science, technology, and public engagement prompted a wide range of stakeholders to argue for a reevaluation of how the underlying principles of the 1976 Belmont Report—respect for persons, beneficence, and justice—were applied to the modern research enterprise.

Charles McCarthy, the first director of the U.S. Office for Protection from Research Risks, noted in 2008 that “[IRBs] have become more insightful and sophisticated…. But unless [the Human Research Protection System] is considered to be an evolving and expanding mechanism, adapting to the problems of each period of history, it is in danger of becoming fossilized and ineffective.”5

Independent review of clinical research by an academic or independent IRB is required for U.S. studies funded by HHS and other U.S. federal agencies, as well as for research testing interventions—such as drugs, biologics, and devices—that are under the jurisdiction of the U.S. Food and Drug Administration.

At its core, the original Common Rule guides 17 federal departments and agencies in determining how:

• research institutions comply with human subject protections; • researchers obtain and document informed consent; and • IRBs establish membership and conduct operations, review of research, and record keeping.

The newly revised Common Rule includes the following five provisions designed to help all IRBs keep pace with the changing nature of research:

1. Establishes new requirements regarding the information that must be given to prospective research subjects as part of the informed consent process. 2. Allows the use of broad consent (i.e., seeking prospective consent to unspecified future research) from a subject for storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens. 3. Establishes new exempt categories of research based on their risk profile. 4. Creates a requirement for U.S.-based institutions engaged in cooperative research to use a single IRB for that portion of the research that takes place within the United States, with certain exceptions. 5. Removes the requirement to conduct continuing review of ongoing research for studies that undergo expedited review, and for studies that have completed study interventions and are merely analyzing study data or involve only observational follow up in conjunction with standard clinical care.

Easing the Burden of the Informed Consent Process

The first provision is perhaps the most significant; it supports the principle of respect for persons.

Over the years, informed consent forms have become “lengthy, dense, and technical,” says David Borasky, Vice President of IRB compliance for the WIRB-Copernicus Group. The Common Rule update is meant to improve these forms and the research experience for participants. How that happens—and whether new forms truly make a difference for participants—is left up to the discretion of each IRB.

While improving the informed consent document is important and could lessen the decision- making burden for participants, “it is the process that determines success,” Borasky says. “If you have a researcher who is really good about implementing the process of informed consent, then this may not have a big impact.”

For clinical researchers who are new to clinical trials, however, improved consent documents could help with recruitment and enrollment. Further, given the high turnover rates among principal investigators, there is substantial need for better resources and training. Members of the Association of Clinical Research Professionals (ACRP) have seen this demand growing, in terms of enrollment in its Certified Principal Investigator (CPI®) program. More information about becoming a Certified Principal Investigator is available on the ACRP website.

Independent IRBs Stand to Gain from Multisite Research Review

Apart from revamping informed consent, the revised Common Rule makes significant changes with its requirement for U.S.-based institutions engaged in cooperative research to use a single IRB for U.S. studies. Independent IRBs stand to benefit from this provision because they are set up administratively and technologically to handle these multisite research projects. Most academic IRBs are not equipped with sufficient staff or resources to serve in this way, says Prentice of UNMC.

Channeling multisite research through single IRBs is designed to increase efficiency for investigators, which is a fundamental goal of the revisions. Too often, says Prentice, “investigators have complained that they can’t participate in research because it takes too long for academic institutions to review and approve” clinical study protocols. By the time they get complete approval, the trial enrollment may be closed.

Therefore, one of the more important provisions of the new Common Rule presently on hold is single IRB review, which has a later compliance date of January 20, 2020. However, it is not clear at this time whether there will be a further delay in Common Rule implementation, which could also push forward the single IRB compliance date. Obviously, institutions are in a situation of regulatory uncertainty.

Clearly, there’s a need for change. In the big picture—considering the 40 years of protecting human subjects in research already accomplished through the Common Rule—waiting another six to 12 months for clarity seems a small price to pay. After all, these reform efforts will support progress in clinical research, public trust in the enterprise, and protection of the participants who make research possible.

References

1. U.S. Department of Health and Human Services. Office for Human Research Protections. 2018. HHS and 15 other federal departments and agencies announce an interim final rule that delays both the effective date and general compliance date of the revisions to the Federal Policy for the Protection of Human Subjects to July 19, 2018. 2. Federal Policy for the Protection of Human Subjects. 2017. Federal Register 82 FR 7149. 3. Public Responsibility in Medicine and Research. 2018. Focus on the revised Common Rule, delay of the revised Common Rule: what does it mean for me? 4. Grady C. 2015. Institutional review boards: purpose and challenges. Chest 148(5):1148– 55. 5. McCarthy C. 2008. The origins and policies that govern institutional review boards (in Emanuel E, Grady C, Crouch R, Lie R, Miller F, Wendler D, eds.; The Oxford Textbook of Clinical Research Ethics p.550; New York, N.Y.: Oxford University Press).

Matthew Harrington is a freelance writer and consultant with Worldwide Clinical Trials.

Clinical Researcher—April 2018 (Volume 32, Number 4)

ICH IN FOCUS

ICH E6(R2) and Data Integrity: Four Key Principles

Michael Rutherford, MS

[DOI: 10.14524/CR-18-4021]

A few months prior to the release of the updated International Council for Harmonization Guideline for Good Clinical Practice (ICH GCP E6(R2)),{1} three draft guidance documents on the topic of “Data Integrity” and an explanatory Q&A document were published by the U.S. Food and Drug Administration,{2} the Medicines and Healthcare products Regulatory Agency (MHRA) in the U.K.,{3} the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme,{4} and the European Medicines Agency (EMA),{5} respectively. Further, in March 2018, the MHRA published its GxP Data Integrity Guidance and Definitions, Revision 1.{6} This is the first of the guidance documents to be finalized and the first with a GxP (for “Good Practices” in different realms) scope.

Data integrity is defined as the extent to which all data (whether electronic or paper-based) are complete, consistent, accurate, trustworthy, and reliable throughout the data lifecycle—from creation through archival status and their eventual destruction. Regulatory agencies, as well as the biopharmaceutical industry, rely on data to ensure subject/patient rights and safety and the scientific value of clinical studies. In this column, we will examine how these documents, with a particular focus on the MHRA final guidance, can facilitate successful implementation of the ICH E6(R2) data integrity requirements.

Data integrity principles are nothing new; however, the addenda in ICH E6(R2) reinforce these principles and the role that monitoring (as redefined by ICH E6(R2)) can and should play in verifying the integrity of data throughout a study. The four key principles of data integrity are highlighted in the following sections. ALCOA+

Data should be Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA). These have historically been considered the attributes of data quality and Good Documentation Practices (GDocP). However, in recent years, an additional four attributes—namely Complete, Consistent, Enduring, and Available (known as ALCOA+){5,6}—have been added to emphasize that the data should also be whole (i.e., include relevant metadata), consistent (e.g., date and time of activities should be in the right sequence), lasting throughout the lifecycle, and readily available for review or inspection. These attributes apply to both paper and electronic records and represent the foundation of data integrity.

Computer System Validation

Computer systems should be validated based on a risk assessment. ICH E6(R2), Section 5.5.3 emphasizes that validation should take into consideration “the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.” In other words, not all systems are the same from a risk perspective, and not all functionality within a system is the same, so the level of effort and resource applied to the validation should be commensurate with the risk.

The same section of ICH E6(R2) also states that, “When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should: (a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance.” Therefore, the user of the system (i.e., the sponsor or the contract research organization acting on behalf of the sponsor) is responsible for ensuring that the system is validated for the user’s intended use when the system is supplied by a vendor.

The MHRA guidance{6} emphasizes that “risk to data may be increased by complex, inconsistent processes, with open ended and subjective outcomes compared to simple tasks that are undertaken consistently, are well defined and have a clear objective.” Other factors which should be considered include the degree of automation versus human intervention, and the ability to alter or delete data and the likelihood of its detection. This guidance goes on to note, “Where there is human intervention, particularly influencing how or what data [are] recorded, reported or retained, an increased risk may exist from poor [organizational] controls or data verification due to an overreliance on the system's validated state.”{6} In other words, the system should not be considered in isolation of the relevant business process—the entire business process and data flow should be considered in the risk assessment. This is a critical concept that is sometimes overlooked.

Access Control

Limiting the ability to record, change, and delete data is a fundamental requirement for assuring data integrity. Roles and associated access types must be defined and assigned to clearly indicate who can do what within the system and business process.

Potential conflicts of interest between roles should also be considered to ensure individuals do not have the capability and functionality to execute steps that can impact data integrity. For example, does an individual have both an administrator and a business role that would allow him or her to circumvent the access controls in place by modifying the system configuration or the data directly?

Roles need to be defined and assigned carefully, to limit access to those who truly require it to execute the tasks that they are responsible for performing. Similarly, user access should be removed in a timely manner once it is no longer required. Routine review of user access should also occur to ensure roles are correctly assigned, conflicts of interest in roles do not exist, and access is limited to only those individuals who require it.

Metadata and Audit Trails

Data integrity principles cannot be discussed without also addressing the fourth principle of metadata and audit trails. Metadata are data that describe the attributes of other data and provide context and meaning. Typically, these are data that describe the structure, data elements, inter- relationships, and other characteristics of data. Metadata also permit data to be attributable to an individual (or if automatically generated, to the original data source). Metadata form an integral part of the original record and, without metadata, the data have no meaning. As a result, metadata should be maintained and controlled in the same manner as the original data to which they belong.

Metadata are often maintained within the audit trail of the system, providing insight into the steps and thought process behind the original data and/or the generation of results. However, all too often, technical system logs are considered equivalent to data audit trails. Technical system logs typically record various system, configuration, and operational events while data audit trails normally record the creation, modification, or deletion of records or data.

For example, an electronic data capture audit trail should capture all changes, including deletions of data related to each subject—including the old value, the updated value, who made the change or deletion, the reason for the change or deletion (if necessary), and the time/date stamp of when the change occurred. Without this information, the principal investigator does not have the full data history before approving the subject’s data.

In-process audit trail reviews should be performed by users of the computerized system as part of the normal business process, and they should be based on a detailed understanding of the process supported by the computer system, the applicable GCP requirements, and the risk to human subject protection and the reliability of the trial results. Per ICH E6(R2), Section 5.18.1(b), part of the purpose of monitoring is verifying that “the reported trial data are accurate, complete, and verifiable from source documents.” In-process audit trail review provides a means of doing this, and should be defined and executed as part of the monitoring activities across the entire study and trial process.

Indeed, ICH E6(R2), Section 5.18.3 emphasizes the importance of centralized monitoring processes to “complement and reduce the extent and/or frequency of onsite monitoring and help distinguish between reliable data and potentially unreliable data.” Audit trail reviews conducted by data managers, statisticians, safety staff, and other roles can help identify missing data, inconsistent data, data outliers, unexpected lack of variability, and protocol deviations; plus systemic or significant errors in data collection and reporting at a site or across sites; and other data integrity issues. Conclusion

The Addendum to the introduction section of ICH E6(R2) states “this guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording, and reporting while continuing to ensure human subject protection and reliability of trial results.” Sites should be examining their processes to ensure that they are meeting the data integrity expectations documented in ICH E6(R2). The draft guidance documents on Data Integrity, the EMA Q&A document, and the final MHRA Guidance document offer very useful insight into how regulators are interpreting their data integrity expectations.

References

1. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonized Guideline. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). Current Step 4 version dated November 9, 2016. 2. U.S. Food and Drug Administration. 2016. Data Integrity and Compliance with CGMP Guidance for Industry (Draft Guidance). https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc es/UCM495891.pdf 3. Medicines and Healthcare products Regulatory Agency. 2016. GxP Data Integrity Definitions and Guidance for Industry (draft version for consultation). www.gov.uk/government/uploads/system/uploads/attachment_data/file/538871/MHRA_GxP _data_integrity_consultation.pdf 4. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme. 2016. PIC/S Guidance: PI 041-1 (Draft 2) Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments. https://www.picscheme.org/en/publications 5. European Medicines Agency. 2016. Data Integrity Q&A. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000027.j sp&mid=WC0b01ac05800296ca#section16 6. Medicines and Healthcare products Regulatory Agency. 2018. GxP Data Integrity Guidance and Definitions (revision 1). https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/687246/MHR A_GxP_data_integrity_guide_March_edited_Final.pdf

Michael Rutherford, MS, ([email protected]) is Executive Director of Computer Systems Quality and Data Integrity for Syneos Health.

Clinical Researcher—April 2018 (Volume 32, Issue 4) Site-Oriented Clinical Kits: The success of a study begins at the point of collection

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One of the primary challenges in conducting clinical trials, especially trials in multiple countries, is the collection and logistics of biological samples. As clinical trials become increasingly complex, sponsors and CROs must find ways to streamline operations to unburden sites and their investigators and keep the focus on the patients. Among the key considerations in this process are:

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The importance of doing it right

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Clinical Researcher—April 2018 (Volume 32, Issue 4)

FXM Research: It’s Not Just Clinical Research! It’s Clinical Research Excellence…Sustained!

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Founded in 2000, FXM Research is a privately owned and operated Clinical Research Site that conducts Phase II, III, and IV clinical research trials specializing in Dermatology. Throughout the years, our ability to deliver aggressive, time-bound enrollment goals, while providing trustworthy data to pharmaceutical companies and contract research organizations (CROs), has earned FXM Research a great deal of notoriety and fame within the Dermatology research industry.

Today, FXM Research’s success is widely regarded throughout our four operating branches: FXM Research Corp., based in Miami, Florida and home of our headquarters; FXM Research Miramar, located in the city of Miramar, Florida; and FXM Research International, including two branches in Belize City, Central America.

Our Mission

At the core of our business and operating systems, our FXM Research mission is to support pharmaceutical companies and CROs with introducing new and U.S. Food and Drug Administration–approved medications successfully into the marketplace. We perform this efficiently and effectively by providing the highest quality service in a timely fashion and at the lowest possible cost.

• We specialize in conducting Phase ll, lll, and lV Dermatology Clinical Trials. • Our primary concerns are subject safety and adherence to the protocol. • Turnover time for regulatory documents, budgets, and contracts is usually 24 to 48 hours. Our Success

We offer experienced, trained, and bilingual personnel (English and Spanish) who interact with our subjects, sponsors, and CROs as a cohesive team.

Our Principal Investigators (PIs) are Board Certified Dermatologists and Certified Clinical Research Investigators with many years of extensive experience. They are located onsite and are available full-time.

Most subjects are recruited from the offices of our PIs’ private practices and/or FXM Research’s extensive clinical database. We draw heavily from a Spanish speaking population, a group often under-represented in clinical trials. We also have continuing extensive experience with a pediatric population.

We do whatever is necessary to accommodate our subjects’ school and/or work schedule, which maximizes compliance and retention. We are confident that we can surpass sponsors expectations relating to cost, subject enrollment/retention, and the quality of our work.

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Francisco Moncada, RN, BSN, CCRC, President

Email: [email protected] fxmresearch.com

FXM Research Corp. FXM Research Miramar

Hector Wiltz, MD, CPI Francisco Flores, MD

(305) 220-5222 Office (954) 430- 1097 Office

(305) 220-5779 Fax (954) 430-5502 Fax

FXM Research International – Belize, Central America

Julitta Bradley, MD & Ines Mendez-Moguel, MD

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Clinical Researcher—April 2018 (Volume 32, Issue 4) Barnett: Are You a QUALIFIED Clinical Research Professional?

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1. International Council for Harmonization (ICH) E6 Guideline for Good Clinical Practice and the U.S. Food and Drug Administration (FDA).