Page 19 | Advarra

Since November 2017, the Advarra team (formerly Chesapeake IRB and Schulman IRB) has been working to integrate our processes and policies, leveraging mutual strengths in technology, regulatory expertise and customer service to provide clients with high quality research reviews and unparalleled efficiencies.

In the last few months we’ve made a lot of progress, and we’ve been keeping in touch with clients via email, website postings and direct communications to make sure you have the latest information on our integration efforts. If you don’t already receive our newsletter, consider subscribing here so you’re sure to receive timely updates.

We are committed to being transparent and communicative throughout this integration so that you have the information you need to continue your work with as little interruption as possible. As part of that commitment, we’ve assembled the following updated FAQ. If you don’t see your question addressed here, please contact your Study Coordinator or Study Manager or email info@advarra.com.

Legal Structure FAQ

1. Is the merger complete?

Schulman and Chesapeake’s merger was completed November 7, 2017. Both companies are operating independently and conducting business under “d/b/a” status while operational integration and IRB harmonization efforts are underway. Advarra anticipates full integration of all operations, IT systems, IRB rosters and service lines by May 1, 2018.

2. What is Advarra’s legal structure?

CS Intermediate Inc. is the parent company to all of Advarra’s entities. The operating company Advarra, Inc. is an Ohio corporation with headquarters located at 6940 Columbia Gateway Drive, Suite 110, Columbia, MD, 21046.

3. What is the relationship between all of Advarra’s entities?

Schulman IRB changed its corporate name to Advarra, Inc. on December 12, 2017. The legal entity name change will extend to all Advarra, Inc. affiliates, including Chesapeake Research Review, LLC.

Both Schulman IRB and Chesapeake IRB will retain d/b/a status for an interim period and continue to operate under the parent company.

Advarra (legacy Schulman IRB), Chesapeake IRB, IRB Services and Falcon Consulting Group are affiliate entities which share the common parent company of CS Intermediate Inc.

4. When will Chesapeake and Schulman be working as Advarra?

Schulman and Chesapeake’s merger was completed on November 7, 2017. Both companies are operating independently and conducting business under “d/b/a” status while operational integration and IRB harmonization are underway. Advarra anticipates full integration of all operations, IT, IRB, etc. by May 1, 2018.

Financial FAQ

1. Will Advarra need to update its registration in client vendor portals?

Advarra’s payment information is the same as legacy Schulman’s, and Chesapeake’s information remains unchanged. Vendors will simply need to update the vendor name. A W-9 is available to reflect the change in name. Requests for Advarra’s W-9 should be sent to AccountingTeam@advarra.com. Should we make a change in payment information for any entity, it will be communicated to all customers and vendors via written notifications that share the new payment information.

2. Is there a W-9 available for Advarra?

Yes, requests for Advarra’s W-9 should be sent to AccountingTeam@advarra.com.

3. Will clients with Advarra contracts have a single point of payment for all invoices (both from Chesapeake and legacy Schulman?)

Currently, each entity has its own banking information. All remittance information is contained on each invoice. The long-standing banking information for each entity remains in place. We are in the process of harmonizing our treasury structure, and any related updates will be communicated to customers in connection with implementation.

4. Are clients being updated to a new fee schedule?

Advarra will honor negotiated fee schedules for clients who have legacy contracts with Schulman and Chesapeake. Advarra will also honor all fee schedules in place from 2017 that govern protocols submitted prior to January 1, 2018. All other clients have been updated to a new Advarra fee schedule, effective January 1, 2018. Fee schedule requests should be sent to BusinessDevelopment@advarra.com.

5. Will there be changes to the method of payment for invoices distributed?

There are no changes at this time. Currently, each entity has its own banking information. All remittance information is contained on each invoice that is sent out. Currently the long-standing banking information for each entity remains in place. We are in the process of harmonizing our treasury structure and all updates will be communicated to customers in connection with implementation.

Contractual FAQ

1. I have an MSA with both Schulman and Chesapeake. What should I expect?

Advarra’s Contracts Team is actively engaging clients who have MSAs with both legacy Schulman and Chesapeake to consolidate under one Advarra MSA.

2. I have an MSA with Chesapeake; what should I expect?

Contracts with Chesapeake Research Review, LLC remain valid; however, Advarra’s contracts team will be issuing amendments to current MSAs to indicate the name change/assignment from Chesapeake IRB to Advarra, Inc. You will receive communication directly from Advarra’s Contracts Team. Questions regarding contract status should be sent to CPG@Advarra.com.

3. I have an MSA with Schulman; what should I expect?

Contracts with Schulman Associates Institutional Review Board, Inc. remain valid; however, Advarra’s contracts team will be issuing amendments to current MSAs to indicate the name change/assignment from Chesapeake IRB to Advarra, Inc. You will receive communication directly from Advarra’s Contracts Team. Questions regarding contract status should be sent to CPG@Advarra.com.

4. I have an MSA with IRB Services; what should I expect?

Contracts with IRB Services remain valid, and currently there are no plans to assign those agreements. Questions regarding contract status should be sent to CPG@Advarra.com.

5. I have an MSA with Falcon; what should I expect?

Falcon Consulting Group, Inc. will be changing its legal name to Advarra Consulting, Inc. This will not affect the validity of these contracts. The Advarra Contracts Team will send out a legal notice of name change in the coming months. There is no action required by current clients. Questions regarding contract status should be sent to CPG@Advarra.com.

6. I have an MSA with Provision; what should I expect?

Provision contracts will be assigned to Advarra Consulting Inc. The Advarra Contracts Team will send out a legal notice of assignment in the coming months. There is no action required by current clients. Questions regarding contract status should be sent to CPG@Advarra.com.

7. I have a Reliance Agreement or Global IAA with Chesapeake. What should I expect?

Chesapeake’s IRB registration with OHRP/FDA will be transferred over to the Advarra (legacy Schulman) registration by May 1, 2018. Once effective, Advarra will contact clients with global agreements to amend their contracts to the Advarra IRB registration.

Once the IRB registration update is complete, clients will notice that approval documents and other templates will be under the Advarra name. Until that point, all documents will continue with the entity to whom they were submitted.

8. I have a Reliance Agreement or Global IAA with Schulman. What should I expect?

Schulman’s IRB registration with OHRP/FDA and its FWA with OHRP have been renamed to Advarra (d/b/a Schulman IRB). Once effective, Advarra will release a Note to File to clients which they should store with their contracts. No other action will be necessary.

9. My contract includes affiliate language. Who are Advarra’s affiliates?

Advarra’s affiliate entities are all legal entities who share the common ownership structure of our parent company CS Intermediate Inc. Those entities include:

Advarra, Inc. (formerly known as Schulman Associates Institutional Review Board, Inc.)
Chesapeake Research Review, Inc.
0988560 BC Ltd. (d/b/a IRB Services)
Falcon Consulting Group Inc. (with pending name change to Advarra Consulting Inc.)
Provision Consulting

Operational Impact FAQ

1. What is the impact of the merger and name changes to 1572s?

The 1572 will not require an update. In accordance with FDA guidance, there are only two situations when a 1572 must be updated:

1. When an investigator is participating in a new protocol that has been added to the IND

2. When a new investigator is added to the study

Since the 1572 is a sponsor form, the sponsor should ensure they have the appropriate contact information for the IRB; the contact information for Chesapeake or Schulman IRBs will not change. FDA is aware of the merger and have indicated that clients should email gcp.questions@fda.hhs.gov with any further questions or confirmation regarding updates to 1572s.

If 1572s have not already been distributed to sites, we recommend the following:

Date	Submission Platform	Acceptable 1572 Entities
Prior to April 30th	Schulman eTools	“Schulman IRB” “Advarra”
Prior to April 30th	Chesapeake CIRBI	“Chesapeake IRB”
After April 30th	Advarra CIRBI Platform	“Advarra” If Schulman or Chesapeake, please reference the Note to File

2. We need to audit Advarra or Advarra Consulting as a new vendor. How should we set this up?

Any customers who wish to audit Advarra as a new vendor may request and schedule an audit by sending an audit request to qualityassurance@advarra.com.

Any customers who wish to audit Advarra Consulting as a new vendor may request and schedule an audit by calling us at 610-363-0815 or sending an audit request to qualityassurance@advarra.com.

3. How is Advarra Consulting ensuring its status as an independent consultant?

While Advarra Consulting will work in conjunction with our other affiliates to deliver Clinical Quality Assurance (CQA), GxP consulting, and Human Research Protection (HRP) consulting services to our customers, Advarra Consulting will maintain a separate legal entity and reporting structure under the Advarra parent company.

4. How is Advarra Consulting avoiding conflict of interest in serving both CROs and Pharma companies?

Advarra Consulting appropriately identifies and separates requests for services from Pharma Companies and CRO’s to make sure that the proposal process, the assignment of resources and the management of project information and reports remain separate and distinct from one another.

5. How will legacy Provision (HRP and GCP) consulting requests be handled from the perspectives of Project Management and Business Development?

The Human Research Protection (HRP) consulting services under Provision have been incorporated into Advarra Consulting. Moving forward, we will contract CQA, HRP and GCP/GXP consulting services under Advarra Consulting. The model for delivery of the services is the same – a dedicated Program Lead will be assigned to oversee the project management and quality aspects of the work and services will be provided by qualified consultants, as appropriate.

A standard operating procedure (SOP) simply and clearly describes how a particular task is to be performed by staff at an organization. When tasks are performed consistently, it allows personnel to be more efficient and productive. In the context of properly maintaining an electronic data capture (EDC) system, standard operating procedures (SOPs) are essential to ensuring regulatory and organizational policies are met. Training for new staff and workload distribution activities are also enhanced by SOPs.

Furthermore, sponsors and other affiliate clients are typically impressed when questions of site performance and processes are addressed in standard operating procedures. However, the actual task of writing an SOP is not always easy. The best examples are simple to read and allow staff to quickly understand how their specific role contributes to the team. So what is the best approach for creating an SOP? The best approach involves developing a plan with all staff members involved with data collection at your institution, and defining the relevant roles and responsibilities. This article will look one recommended approach for creating an SOP.

1) Collect a list of required activities

Start by collecting a list of activities that are required. Ask staff members who are involved with data collection to provide this list. This means that if your site has two to three people involved with data collection on any given study, ask them to write down steps that they typically accomplish with each study. Try to fill in the gaps and answer questions as they come up. The goal is to provide this SOP to anyone at your site, so they can clearly understand responsibilities and timelines. In the beginning, don’t be overly concerned about making the process more efficient or easier to follow. That piece will come down the road.

2) Write and review an initial plan with staff

It is important to stress that all people involved in doing the tasks and procedures should be involved in the writing and review of the initial SOP development plan. You may want to hold a meeting with staff members to critically evaluate and review tasks. This is the part where things can become interesting, especially when there are differing ideas about what is important and what tasks are not as critical. It’s important to remain impartial as a leader and reassure everyone that these types of issues are the basis for further development and evaluation of site SOPs. Acknowledge everyone’s ideas and feelings and never say, “You’re wrong!” This is simply a recipe for disaster for the team. However, it’s critical to keep ideas moving and remind the group that, out of respect for everyone’s time, you must move forward with new topics so that the group stays focused on the goal.

When drafting tasks and responsibilities, it can also be useful to write on a large sheet of paper (and don’t be afraid to use multiple pages if necessary). This helps everyone visualize different concepts and procedures, and then allows them to draw their own lines and connections between items.

The best way to wrap up the first meeting with your team is to set aside some time for brainstorming. This can help you to summarize and add additional steps. Individuals generally enjoy brainstorming and giving some extra time allows people to be more creative. While at the same time this approach doesn’t completely bore others who have a hard time with this phase.

3) Draft a detailed list of steps for the SOP

Once a handsome list of tasks is gathered, organize it into chronological steps. It can be advantageous to hold another meeting with the group once this is finished. But before you meet again with the group, ensure the secondary steps are listed as a process flow chart. Add a few sticky notes for tasks that could be rearranged, so others might be able to easily move items.

4) Begin testing among the group

Once the final list of steps is reviewed by the group, provide copies to the team and start testing. This allows the group to critically evaluate the SOP by using the steps listed. Does it work? Add any missing items and facilitate a discussion about redundant or unnecessary steps that could be eliminated. In order to wrap up the activities of SOP writing, it is typically necessary to introduce the concept of a “guideline” to the group. What is a guideline and does it differ from an SOP? Read on to learn more.

Additional Considerations for SOP Creation:

Separate guidelines and SOPs

Guidelines are detailed descriptions of the processes and further explain activities within the organization. An SOP generally does not need to be updated frequently, whereas guidelines might need more frequent updates. Having two separate categories allows the group to focus on global issues separate from local or smaller details that might need to be changed due to other policies. An advantage to separating out these documents is that it allows smaller teams to provide much greater details on activities. Another advantage is that if there are changes to an application or a program update, the SOP can typically remain unchanged, but the specific details of the tasks listed in the guidelines are updated accordingly.

Consider generally accepted SOPs for data collection

Overall there are two main SOPs for this topic that are generally used and that cover all aspects of data collection. These are “Correcting CRFs and source document errors” and “Handling of case report forms (CRFs).” The corresponding guideline documents should go into further details on roles and responsibilities while ensuring all activities have corresponding assignments to individual team members.

Don’t be afraid to start from scratch

Oftentimes it is difficult to see the accurate picture of how tasks should be completed unless you avoid looking at the old template. The previously created documents might not reflect current company culture and if the goal is to create a fresh and clean approach, then starting from a blank document is useful. It’s not like recreating the wheel, it’s avoiding using old paradigms.

Don’t confuse SOP creation and compliance with 21 CFR Part 11

While compliance with 21 CFR Part 11 is important to consider while developing an SOP, there are many requirements associated with the regulation that go beyond the scope of creating an SOP for data collection.

Additional resources

Standardized SOPs can be crucial to maintaining consistent data collection practices across clinical trials at your organization. However, data quality is also dependent on the knowledge and experience of those involved in the data management process. While many clinical researchers devote some of their time to data management tasks, optimal data management requires trained and qualified professionals who are committed to upholding quality data standards.

This blog post was originally published on October 14, 2013.

Discover how Advarra EDC ensures data security and integrity using audit trails and secure signatures to fully support validation and compliance with 21 CFR Part 11.

On November 7, 2017, we announced that Chesapeake IRB and Schulman IRB are merging under the new organizational name, Advarra. Our teams are excited to work with a like-minded organization and for the new opportunities this merger offers, and the overwhelmingly positive response we’ve received from the research community thus far reaffirms our confidence in the value of this venture.

We understand that questions and uncertainty often spring from big changes like the merger of two large, industry-leading organizations. As we proceed through the integration process, we are committed to providing proactive answers and support to our clients. We will be transparent and communicative so that you have the information you need to continue your work with as little interruption as possible.

To that end, we’ve assembled the following FAQ to address some of the most commonly asked questions about this merger. If you don’t see your question addressed here, please contact your Study Coordinator or Study Manager or email info@advarra.com.

Stay tuned for further integration information via email, blog and other communication formats.

Integration FAQs: The Basics

Q: What will happen to my existing studies?

A: Over the next few months, there will be no changes to currently active studies. They will remain with the IRB that originally reviewed the study, and any written IRB correspondence/documentation will be issued from the reviewing IRB. Your current study contacts and timelines will not be affected.

As Chesapeake IRB and Schulman IRB progress through the integration process, we will be harmonizing and optimizing our processes, technology platforms and standards of practice to ensure our combined clients are provided with and have access to the most efficient, customer-focused and highest quality service provider in the industry.

Q: Do I have to use a different submission form or system?

A: Please continue to use the current submission forms and processes for Chesapeake IRB and Schulman IRB. There will be no immediate changes to the Chesapeake IRB and Schulman IRB submission platforms and processes.

As Chesapeake IRB and Schulman IRB progress through the integration process, we anticipate migrating to a common electronic platform to better serve our clients. Changes will be communicated and coordinated with you in advance. Any training needs will be provided on a routine and ongoing basis.

Q: Will there be any changes to existing contracts?

A: All existing confidentiality agreements, MSAs and contracts remain valid, and the terms of these agreements will continue to be observed. As new agreement templates are developed for the combined organization, we will coordinate any changes with you directly.

Q: I have fee schedules for both Chesapeake IRB and Schulman IRB. Can I use either one?

A: Chesapeake IRB legacy fee schedules will apply to submissions through the Chesapeake IRB platform, and Schulman IRB legacy fee schedules will apply to submissions through the Schulman IRB platform. Your Business Development representative will be happy to assist with any rate card or invoicing questions.

Q: Will you maintain your AAHRPP accreditation?

A: Yes, there will be no changes to our AAHRPP accreditation statuses.

Q: Will we need to update our FDA 1572 or Federalwide Authorization (FWA)?

A: All FDA 1572s and FWAs listing Chesapeake IRB and Schulman IRB remain in effect. If any updates are required moving forward, we will provide proactive guidance on changes necessary to meet regulatory requirements.

Q: Will my primary contact change?

A: Please continue to communicate with your existing primary contacts at Chesapeake IRB and Schulman IRB. We will proactively communicate and coordinate any changes in personnel assignments.

Q: Will the composition of your review boards change?

A: All of the existing review boards for Chesapeake IRB and Schulman IRB will remain in place.

As integration proceeds, Chesapeake IRB and Schulman IRB boards will have access to the expertise of each other’s board members, providing even greater resources and expertise for the review of your study.

Q: How long do you expect integration will take?

A: We anticipate the integration process will take several months and up to a year to complete. Any changes to policies and procedures that impact you will be communicated to you in advance.

Q: Will there be any delays to my submissions?

A: There will be no impact or delays to your study submissions. Current processes and review boards will remain in place. All of our integration planning and efforts are focused on making sure the work gets done with the same industry-leading quality and timeframe you have come to expect.

On October 1, 2017, NIH’s policy for certificates of confidentiality (CoCs) changed so that CoCs are now automatically issued for all NIH-funded research that collects or uses identifiable, sensitive information. Previously, CoCs were issued by NIH on request and only for research that involved information that, if disclosed, could have adverse consequences for subjects or damage their financial standing, employability, insurability, or reputation. The categories of covered research have been expanded and applicability now depends on the potential for participants to be identified rather than on the nature of the research.

This change to the NIH policy complies with the requirements of Section 2012 of the 21st Century Cures Act and applies to all research that was commenced or ongoing on or after December 13, 2016.

Definition

If you’re not already familiar with CoCs, here’s a quick explanation: A CoC helps to protect the private information of research subjects by prohibiting researchers from disclosing identifiable, sensitive information unless:

Required by federal, state, or local laws (such as communicable disease reporting);
The subject consents to the disclosure; or
The disclosure is made for the purposes of scientific research that is in compliance with human subject regulations.

Importantly, this means that the CoC prohibits disclosure in response to legal demands, such as subpoenas. Its protections go beyond the standard confidentiality safeguards found in the regulations.

A CoC applies not only to the researcher conducting the NIH-funded study but also any subawardees as well as anyone who receives a copy of the information protected by the CoC policy, even if they do not directly receive the NIH funds.

So what does this mean for researchers? Let’s look at some key impacts:

Informed Consent Forms and Participant Notification

CoCs previously were issued by NIH only upon receipt and approval of a CoC application, so only informed consent forms (ICFs) for these studies included information about the CoC’s protections.

Now that CoCs are issued for all new and ongoing NIH-funded research that collects or uses identifiable, sensitive information, researchers must include the CoC information in these ICFs. For ongoing studies that did not have a CoC but now qualify for one and are open to enrollment, this will require a revised ICF for prospective participants to sign. However, re-consent of subjects who signed the previous consent form does not appear to be required by NIH. Advarra will generally not require re-consent in these situations but will assess the investigator’s proposed plan for participant notification on a study-by-study basis.

NIH has developed suggested ICF language describing the CoC protections, available here.

Determining Whether a CoC Has Been Issued for an NIH-Funded Study

Because NIH is now issuing CoCs as described above, it will no longer provide researchers with a physical certificate and generally will not indicate whether a specific study is subject to a CoC. Instead, NIH advises that the Notice of Award, the NIH CoC Policy, and the NIH Grants Policy Statement will serve as documentation of the CoC. Therefore, investigators and institutions will be responsible for determining whether their study is subject to a CoC. This determination is to be based on whether the NIH-funded research collects or uses “identifiable, sensitive information.” This is a new standard and it does not appear to limit the categories of covered research to information traditionally considered sensitive, such as that obtained during mental health or drug use research. Instead, the policy defines, “identifiable, sensitive information” as:

“[I]nformation about an individual that is gathered or used during the course of biomedical, behavioral, clinical, or other research, where the following may occur:

An individual is identified; or
For which there is at least a very small risk, that some combination of the information, a request for the information, and other available data sources could be used to deduce the identity of an individual.”

The second part of the definition – “at least a very small risk” that an individual’s identity could be deduced- is new for the research community. Importantly, it does not align with either the Common Rule or HIPAA definitions. As a result, there are lingering questions regarding what this definitional phrase means and exactly at what point of identifiability the CoC protections kick in.

Questions and Challenges

How Will Ongoing Research be Impacted?

The new CoC protections apply to all research ongoing as of December 13, 2016, and this includes research that was previously issued a CoC by NIH. Guidance will be needed regarding how to manage these studies, including any prior disclosures or ongoing use of the information that was previously acceptable but will now be prohibited. This is further complicated by the fact that secondary researchers receiving information protected by a CoC must also uphold the protections of the CoC.

2. Who Will Provide Oversight?

Who decides whether information is “identifiable, sensitive information” triggering CoC protections? Under what specific criteria? How are ongoing studies now subject to CoCs managed? How are impacted studies tracked?

One of the major changes under the policy is that responsibilities are now shifted to the investigator. Especially in light of the many outstanding questions (some of which have been raised here), this will require a proactive and systematic approach at the institutional level.

Need more information on CoCs? Review NIH’s FAQ page on CoCs.

Need assistance implementing these changes at your organization? Advarra Consulting can help.

Food and Drug Administration (FDA) regulations and the Common Rule require that the selection of participants in research is equitable. “Equitable selection” generally refers to the idea that no one group should bear all the burdens of research or reap all the rewards. This term also refers to the idea of ensuring marginalized populations have access to research.

These regulations also require that research include additional safeguards when some or all of the study participants are likely to be vulnerable to coercion or undue influence.

The principle of equitable selection and the requirement for additional safeguards for certain vulnerable groups can seem at odds. We see this tension in the example of adults with impaired decision-making capacity. While these adults might be considered vulnerable to coercion and undue influence, and thus in need of additional protections, institutional review boards (IRBs), sponsors, and investigators must also be cognizant of not unduly limiting these individuals’ research participation in an effort to protect them.

Putting It Together: Neurological Disease Research Example

Consider the example of research on neurological diseases. Researchers continue to chip away at this challenging field, seeking new treatments and potential cures for these conditions. This research is urgently needed: In the U.S., neurological diseases create nearly $800 billion annually in healthcare costs. The economic, social, and emotional costs of these conditions will continue to grow with our aging population.

When conducting clinical research on neurological diseases, researchers often must provide additional safeguards for the research participants. Conditions like Alzheimer’s disease, Parkinson’s disease, and others can cause both physical and mental impairment, making individuals vulnerable to coercion or undue influence.

Researchers must be careful to ensure individuals with impaired decision-making capacity (and, if appropriate, their legally authorized representatives) are fully informed about a study and can provide legally effective informed consent to participate in research. A legally authorized representative (LAR) is any individual, judicial body, or other body who are authorized under applicable law to consent to research participation on behalf of a designated person (45 CFR 46.102(i)). Depending on where the research takes place, an acceptable LAR might be a health care proxy, medical power of attorney, or a caregiver.

Understanding “Capacity”

In this context, “capacity” refers to a potential research participant’s ability to:

Make and express a choice
Understand relevant information
Appreciate the significance of the information relative to the participant’s own situation
Reason with this relevant information in making decisions

Decision-making capacity is a spectrum, with some individuals more capable of understanding and reasoning than others. With this in mind, “impaired decision-making capacity” can include anyone who is incapable of giving legally effective informed consent. This could be because of a neurological condition that affects an adult’s decision-making capacity, a developmental disability (e.g., autism spectrum disorder), an injury leading to temporary incapacity (e.g., an injury that causes someone to become unconscious), or even because a person has been put under legal guardianship by a judicial body.

Don’t assume that just because an individual’s decision-making capacity is diminished that he or she cannot provide legally effective consent. Decision-making capacity is variable within groups and may change throughout the course of a study: Someone with early Alzheimer’s disease may be capable of providing consent, but as the disease progresses, their capacity will likely diminish.

Regulatory Guidance

In its draft guidance Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors, the FDA recommends additional safeguards for participants with diminished decision-making capacity, such as:

Using an independent “qualified professional” to assess the consent capacity of potential participants at the time of consent and in an ongoing manner
Establishing a waiting period to allow additional time for decision making
Using methods to enhance consent capacity, such as repetition, simplification, and/or enlisting a participant advocate or trusted family members
Using questionnaires to assess understanding
Reassessing a participant’s decision-making capacity for progressive disorders
Involving LARs as cognition declines
Including an assent mechanism
Involving the IRB or another third party to observe the consent process and/or the research

Vulnerabilities like impaired decision-making capacity are critical aspects of clinical research. Vulnerabilities have driven the regulations governing research, and honoring that mandate gives us continued permission to conduct research.

Regulations can’t cover every person or situation, so it’s essential for research professionals to have a working mental construct for identifying vulnerability, along with practical ways to mitigate its influencing factors.

Note: This article was originally published on August 30, 2017, and has been updated to include new and clarifying information.

At Advarra we’ve been seeing more and more eConsent studies recently, which is great—eConsent technology can often better inform participants than just the traditional paper consent, which is great from an IRB perspective. We also now have federal guidance on how to implement eConsent in clinical research, making it a bit easier to implement the technology.

Given the steady increase in eConsent review, Advarra’s IRB and operational staff have been examining our processes to make sure we’re providing efficient, compliant review services for eConsent studies. We’ve learned a lot about eConsent since we first started working with the technology, and we’d like to share some of those learnings with our colleagues in the research community.

It’s a Diverse Field

eConsent comes in a variety of flavors: we’ve seen some studies with an entirely electronic consent process, studies that incorporate only certain elements of eConsent (like video or electronic content delivery via iPads or laptops), and everything in between.

With so many options available, it’s important to think about each study individually and how eConsent will impact the informed consent process. Here are a few impacts to consider:

Will your participants be comfortable with an entirely electronic consent conversation?
What kind of information is best presented electronically?
How will research staff support the eConsent technology and process?
How will new information be shared with participants?

Consider what you want the eConsent to do for your study, who will use it and who will benefit from it, to help ensure you’re assembling a tool that will be truly beneficial for your study.

IRB Review of eConsent Is Sometimes Clunky

For the IRB, reviewing an eConsent is quite different from reviewing a paper-based consent. Unlike with electronic patient reported outcome (ePRO) systems, where the IRB only approves the content, the IRB reviews the eConsent content and the eConsent platform.

This means reviewing just a Word doc of eConsent or screenshots content is not sufficient—the IRB needs to also review the content in the same context as a participant will review it, so the IRB needs to see the eConsent system including any hyperlinked or interactive portions as well.

Reviews can become tricky when the IRB needs to transmit notes on or request changes to an element of the eConsent—it’s often not as easy as turning on tracked changes or using electronic sticky notes. While some eConsent vendors have built IRB review tools into the eConsent system, which allow the IRB to review and request changes directly within the eConsent platform, many still rely on old standards like Word and PDF documents to submit content for IRB review.

This can lead to delays in the review process: for example, the IRB may provide its feedback via tracked changes in a Word document, and that feedback must then be applied to the eConsent system. Then the updated content must be re-submitted to the IRB (either using the eConsent system itself or another Word document) to confirm that the requested changes were in fact applied. These extra steps can lead to potential data entry errors and add extra time to the overall review process.

Keep in mind too that the regulations require IRBs to maintain the version of any web-based information containing the study-related information that the IRB has reviewed and approved. This includes text-based information as well as information provided via video, infographics, hyperlinks to external resources and other multimedia sources.

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.

Version Control Can Be Challenging

Many IRBs use version control notations to track which version was approved by the IRB and which version study participants should be using. This version control notation may be referenced in approval documentation to confirm what has been approved, a helpful resource when working with an ICF that has been revised multiple times. Version control notations can also be helpful when the IRB archives materials for a closed study.

With paper-based consents, the IRB typically generates the final product (the approved ICF) so the IRB can also easily apply its standard version numbering system to the ICF. This is not possible with eConsent, as version control options vary depending on the vendor. IRBs will need to work with eConsent vendors and sponsors to figure out a good way to track versions in an eConsent format and archive each approved version.

eConsent Is Getting Better and Better

While we’ve found some ways eConsent could be improved (at least from an IRB perspective), eConsent as a whole has improved a lot over the past few years. We’re seeing innovative ways to check participant understanding (including quizzes and “spot-check” questions) and inventive methods for providing tiered information, allowing participants to dig deeper on certain topics.

We’re also seeing a wider acceptance and increasing comfort levels with receiving information digitally (as opposed to on a printed page). So while eConsent may not work for every study and every subject population, it’s certainly a worthy option in many circumstances.

It’s 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. But we still have much figure out with the logistics of using eConsent, and collaboration and communication between IRBs, study sponsors, researchers and eConsent vendors is critical. It may benefit be beneficial for IRBs and eConsent vendors to meet and discuss the details of potential review challenges, and at Schulman we welcome the opportunity to collaborate in this way to work toward an efficient and thorough review process. eConsent may take more time than the traditional paper-based consent process, but it’s worth it.

The completion of the human genome project and advances in genetic engineering have paved the way for clinical trials involving human gene transfer, colloquially known as gene therapy research, to enter the mainstream. Gene therapy research involves the deliberate transfer of engineered genetic material to humans, with the goal of compensating for genetic mutations, conferring the capability to produce potentially therapeutic substances, or eliciting immune responses to fight disease.

While genetic engineering brings hope for new medical breakthroughs, the technology is not without risks. Scientists have looked to nature to find an efficient way of delivering genetic material to target cells and found viruses to serve as unlikely allies in the fight against disease. Viral infection involves the transfer of the virus’ genetic material to host cells, making viruses ideal tools for gene transfer once the viral genes responsible for viral replication and disease are removed. While genetically modified viruses have a greater safety profile than the naturally occurring unmodified variety, they remain infectious and capable of posing risks.

NIH Guidelines require a thorough risk assessment be performed prior to conducting research with genetic engineering to ensure the risks are identified and adequately mitigated. Clinical trials involving human gene transfer that have been funded by the NIH or take place at sites that have received NIH funding must comply with the requirements outlined in NIH Guidelines. To assess and monitor the risks surrounding human gene transfer research, NIH Guidelines require institutional biosafety committee (IBC) review—in addition to review by an institutional review board (IRB).

What Is an IBC?

Both the IRB and IBC focus on risk, but the committees have contrasting responsibilities. While IRBs are tasked with protecting the rights and welfare of research participants; IBCs seek to protect study personnel, the community and the environment from exposure to engineered genetic material and other biohazardous agents. An IBC may also advise the IRB to aid in the assessment of risks to the study subjects. IBCs are locally based at the research site and comprised of membership possessing expertise in genetic engineering, biological safety, infectious diseases and environmental protection. Each IBC is required to possess at least two community members who are unaffiliated with the institution or research site and represent the interests of the community and the local environment.

In reviewing a study, IBC members assess the facilities, procedures, safety practices, training and expertise of personnel involved in the research. The committee also assesses the research itself, including the characteristics of the proposed genetic modifications, microorganisms that may be utilized and the target cells, tissues or organs which will ultimately be affected. Facility inspections are required as part of the approval process as well as periodic reviews to ensure appropriate safety measures remain in place.

NIH Guidelines were revised effective April 2016 to bestow greater authority on the reviewing IBC (or IRB) clinical trials taking place at the initial study site. These local oversight bodies perform the initial determination of whether the research poses novel risks which merit review by the NIH Recombinant DNA Advisory Committee (RAC), a national panel of experts in genetic engineering, infectious diseases as well as occupational safety and environmental protection. RAC review is necessary in cases where:

A new vector, genetic modification or delivery methodology is being used that represents a first in human experience and poses unknown risks or
The pre-clinical safety data was produced with a new model of unconfirmed value or
The proposed genetic modifications or delivery methods are associated with possible toxicities that are not widely known.

My Study Needs IBC Review—What Do I Do?

Be proactive in checking with your institution. Some sites such as universities and academic medical centers may already have IBCs in place to monitor basic science or pre-clinical studies; however, these IBCs may or may not be prepared to review clinical research. The latter may result in unnecessary frustration and costly delays.

If your institution does not have an IBC or requires additional expertise, there are a few commercial IBC services available. Keep in mind, however, that an IBC must include a local component. NIH Guidelines do not permit IBC review to be centralized in the same manner as IRB review. Commercial IBC services may create and externally administer an IBC for the site and provide efficiencies over purely local oversight.

IBC review is a new concept to many clinical researchers, but it shouldn’t be an obstacle to research. Include IBC review in your study planning to ensure your research is conducted safely, responsibly and without start up delays.

A major element of any IRB review is the examination of potential benefits and risks to study participants. In studies involving multiple interventions and/or placebo, applying component analysis can help IRB members understand the different levels of risk associated with each intervention.

Component analysis differs from an overall risk assessment, in which a study’s combined interventions and procedures are evaluated as a whole. In 1978, the National Commission stated, “To determine the overall acceptability of the research, the risk and anticipated benefit of activities described in a protocol must be evaluated individually as well as collectively.” Component analysis recognizes that each intervention may have different risks and may or may not offer direct benefit to study participants.

One way IRBs commonly apply component analysis is in evaluating research involving vulnerable subject populations like children, pregnant women, prisoners, and others. FDA and OHRP regulations require that research involving vulnerable populations include additional protections to ensure those vulnerable participants are not exposed to undue risk. In studies with multiple possible interventions or arms, component analysis can help uncover the greatest possible risk a participant could encounter.

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Let’s dive a little deeper and examine how component analysis may be applied to research involving children. FDA and OHRP regulations for pediatric research define four categories of approvable pediatric research, using the criteria of minimal risk and potential for direct benefit to determine the review process and possible additional requirements.

In 2013, the FDA stated that in pediatric research, a placebo cannot be evaluated to offer the prospect of direct benefit to participants. So for pediatric studies involving multiple interventions and/or placebo, each procedure should be evaluated individually to determine the highest possible level of risk study participants may encounter.

Here is an example to illustrate:

Researchers plan to conduct a blinded, randomized, placebo-controlled study of an investigational oral flu preventative drug in healthy children 12-16 years old. The protocol requires a physical exam, administration of the investigational product (IP) or placebo, two nasopharyngeal swabs, and a flu symptom questionnaire. Component analysis asks the IRB to individually examine of the study’s possible interventions: participants will either receive the investigational product or a placebo.

Children receiving the IP will be exposed to research involving greater than minimal risk, as the nasopharyngeal swabs go past the nares and present risk slightly greater than what the average child would experience in daily life. Additionally, the IP presents the potential for direct benefit to the participants.
- The IP arm of this study meets the requirements for approval category 2. Only one parent’s consent is required for this category.
Children receiving placebo will also be exposed to research involving greater than minimal risk because of the nasopharyngeal swab procedure. However, placebo cannot present the potential for direct benefit, though the study may yield generalizable knowledge about the participants’ disorder or condition.
- The placebo arm of this study meets the requirements for approval category 3. Both parents’ consents are required for this category.
Because this is a blinded, placebo-controlled study, researchers won’t know which participants will receive the IP versus the placebo. In this example, the IRB applies approval category 3 to the entire study and requires both parents’ consents be obtained.

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The regulations require IRBs to ensure that risks to study participants are minimized, and “risks to subjects are reasonable in relation to anticipated benefits, if any” (45 CFR 46.111[a] [2]). By using component analysis, IRBs help to ensure that study participants are appropriately protected no matter what the study design.

The popularity of adaptive design in clinical research continues to grow. Adaptive design can be more efficient than traditional study design, and it can help speed decision making. Considering these benefits, plus the ever-increasing cost of conducting clinical research, it’s no wonder adaptive design is so appealing to researchers.

Adaptive design may involve changes to study eligibility, treatment arms and regimens (like dosage and duration), randomization procedures, schedule of events, primary and/or secondary endpoints, and other elements of a study all on an on-going basis. Consider the following characteristics of good adaptive design:

It is proactive—changes are made based on pre-planned decision points in the study, not unplanned reactions to things that happen as the study moves along.
It does not reduce the study’s integrity.
It provides benefits or enhancements to the overall study design strategy.
Adaptations are typically based on study data.
It can be carefully and safely implemented.
Depending on the situation, it can involve clinical, statistical and/or regulatory aspects of a clinical trial.

IRBs that continuously review changes in research can certainly understand the need for innovative approaches like adaptive design. When reviewing a study that incorporates adaptive design, an IRB will need to pay particular attention to the study’s scientific validity, subject safety, informed consents, and the research site’s qualifications. One problematic area is that the risks for subjects may well change when the design of the study changes. For each of these elements, I’ve assembled typical questions an IRB may ask during review. These may also be useful for researchers to consider as they develop adaptive design studies.

Scientific Validity

Are basic good design principles (like those listed above) in place?
Is there a benefit to the adaptive design?
Is there sound design that will answer the research question(s)?
Has bias been introduced by the adaptive design?
Does blinding, where appropriate, remain intact?
Will the results reflect the target population?

Subject Safety

Is there adequate preclinical data to support the design?
Are the right safety measures and monitoring plan in place?
Is there appropriate data and safety monitoring?
Are adaptive options clearly and definitely described?
Are things like safety criteria, stopping rules, maximum doses, and other protections well defined?
How are dosing schedules described in the protocol?
Is there sufficient time to assess safety data prior to decision points?
Who will be making the decisions at the decision points?
How are decisions documented and reported?
What are the contingency plans if safety issues should arise?

Informed Consent

In addition to standard requirements, IRBs will also consider how the informed consent form (ICF) addresses the following:

The design’s level of complexity
- Break it up where possible to help ensure comprehension
Differences between treatment arms
- Include risk language that relates to the individual participant’s participation
Design elements that address safety
- Communicate boundaries and safeguards
How treatments are assigned
- Do participants have a choice?

Bear in mind that describing the expected changing nature of the research in the ICF can be challenging.

Research Site Qualifications

Expertise of the principal investigator and his/her staff
Experience levels are appropriate for the complexity of the design
Staffing levels at the site and experience
Facilities and equipment are appropriate for the particular study
Emergency readiness
Contingency plans

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Adaptive study design can be a smart and effective strategy that offers many benefits. When developing a study with adaptive design, be sure to pay close attention to these added complexities to help ensure participants are appropriately informed and protected.

Clinical trials are often under way before the site and sponsor truly have the information necessary to ensure the study will be productive downstream. There is a great need to improve how things are done upfront during feasibility to ensure success during activation and beyond. Here are a few ways sponsors can improve the feasibility process and get the best possible information from sites.

Explain the goal of the questionnaire to the site

Sponsors need to be clear about what they hope to ascertain when they send out feasibility questionnaires.

If the protocol is in development, are you seeking information that would help answer critical questions about the study design or eligibility criteria?
Are you simply looking to assess the site’s interest and enrollment potential?
Are you trying to obtain some operational information related to the site’s infrastructure?
Or, is it some combination of the above?

Depending on the goals of the sponsor and the timing of protocol development and site selection process, needs and priorities may vary. However, the more the site knows, the more intelligently they can think about the information to determine if they can fulfill your goals.

Give the site enough time to put together thoughtful answers

It’s common for feasibility questionnaires to be sent to sites with the requirement to be completed within 48-72 hours (though as little as four hours has been reported). To help drive a successful protocol design or site selection decision, sponsors need to be more proactive in giving sites the time they need to get the best possible answers. If you ask sites for the world in only a couple days, they will not have enough time to prepare in a way that will truly help anyone in the long run. Rather than trying to get through the initial phase as quickly as possible, focus on preparation and planning.

Make simple changes to your traditional feasibility questionnaire

It’s no secret sites find the current format of most feasibility questionnaires very difficult. To make the process easier:

Don’t have all fields marked as required. Allow sites to skip around questions if it’s an electronic questionnaire.
Allow comments and free text spaces. Give sites a way to complete the survey with additional information. While you may think you’re doing sites a favor by creating simple electronic forms, limiting the type of information sites can share may potentially lead to incorrect data. Allow sites to elaborate on information, as it may not be easily answered by using a single number in the data entry field.
Don’t assume there’s only one PI at a site. Take into account that there could be a large group with multiple sites and/or PIs.
Don’t send out a survey that can’t be printed. Many sites want to review the questions before answering them.
Provide contact information. Include email and/or phone on the questionnaire for someone who can answer questions about the protocol. Questionnaires need to capture the correct data, and to do so, sponsors must make it possible for sites to provide the right information.

Don’t start from scratch each time

Sponsors recognize they need to stop reinventing the wheel each time they do trial feasibility. To do this, use data collected from sites from prior projects and track site capabilities in a database to eliminate the need for sites to complete redundant information over and over again when being considered for a trial. This includes years of experience, type of studies conducted, infrastructure (staffing, facilities, equipment), etc. In turn, this enables sites to use the time they spend during the feasibility stages for more value-added activities, like conducting more robust enrollment validation efforts truly driving study success.

Identify the right point person from your organization that can answer sites’ questions.

Don’t replace all human contact with a survey. There needs to be a mix of automation and human communication. If sites have questions about feasibility, who can they talk to? Contact information should be available on the questionnaire, however, sites often find the contact listed doesn’t have the ability to answer questions. It would be best if the point of contact is the person responsible for the feasibility, and they should be available to answer questions.

Additionally, the CRO needs to be able to answer all questions, as sites become frustrated when the CRO isn’t knowledgeable about the protocol. Simple answers may seem more efficient, but sometimes it helps to have a conversation to help clarify or provide additional information. If you do not have a single person who can answer the majority of questions, provide a mechanism or point person who can get the right answers. A personal relationship will build a lot of trust with a site. The better and faster you can support the site in getting the information they need, the better and faster you can plan for your trial.

Follow up with every site that submits a feasibility questionnaire

After the initial feasibility assessment process occurs, many weeks or months may pass from the time the site provided the initial responses to when the sponsor finalizes the protocol and establishes the study budget. In many cases there is no systematic follow-up by either party to assess the status, timeline or result of the feasibility assessment. If you need additional information from a site, follow up with them. The majority of times, sites not selected never hear back from the sponsor or CRO and have no idea why they weren’t chosen.

Did they not have enough potential patients?
Did they not have enough experience?
Did they not have adequate facilities and staffing?
Or, were there protocol, investigational product or other issues that impacted the decision and had nothing to do with the site?

The absence of such information and lack of transparency and closure leaves the site wondering why they invested all that time and effort to submit the questionnaires and also prevents them from applying any learnings to the next study opportunity.

In 2016, the NIH policy on IRB review for multisite research brought a new-ish term into the clinical research lexicon: “single IRB review,” or “sIRB review.” This term seems to be on its way to replacing “central IRB” or “cIRB” in discussions about one IRB review conducted on behalf of all (or most) participating sites in a multicenter study.

What’s going on here—is sIRB a new term? Is there a difference between sIRB and cIRB review?

As far as we can tell, “single IRB review” and “central IRB review” mean the same thing: a single IRB of record overseeing all clinical trial sites participating in a multisite study.

The reasoning behind these different IRB terms may depend on who is using them, and their physical proximity to the IRB in question. Entities that do not have internal IRBs, like a pharma company or a CRO, may refer to an IRB as a “central IRB” or “single IRB” or “local IRB.” An institution would most likely refer to anything other than their local IRB as an “external” IRB (potentially encompassing both independent IRBs as well as IRBs at other institutions).

While we don’t know for sure, it’s possible that NIH chose “single IRB” because “central IRB” has developed connotations of “independence” from a specific institution—for example, Advarra is an independent commercial IRB, and NCI’s CIRB is an independent federal IRB. In the NIH policy, a designated “single IRB” may be either completely independent OR associated with an institution.

Ultimately, none of these terms are entirely precise. To be clear, when you’re talking about the IRB overseeing participant protections for a given study, you’re talking about the “IRB of record.” This is the term we see most consistently in federal agency guidances, correspondence and other documentation. In using the term “IRB of record,” we focus on the IRB’s responsibilities, which are much more important than the IRB’s arbitrary location or organizational relationship.

It is likely we’ll be seeing a lot more “single IRB” and “sIRB” usages elbowing “central IRB” and “cIRB” out of our shared vocabulary. No matter what you call it, it’s clear that centralized IRB review of multisite clinical research is here to stay. However, whether you’re working with a sIRB, cIRB or local IRB, just be sure you’re clear on the responsibilities assigned to the IRB of record and the responsibilities retained by individual sites.

If you’re new to electronic data capture (EDC) systems, hopefully after reading this you’ll have a basic understanding of the EDC system and its role in clinical trials.

What is an EDC system?

To put it simply, an Electronic Data Capture (EDC) system is software that stores patient data collected in clinical trials. Data is typically first recorded on paper and is then transcribed into the system and saved in an electronic case report form (eCRF). More and more clinical trials are making the move to EDC software and replacing paper records with electronic records. Sponsors, contract research organizations (CROs), and sites have adopted EDC systems to carry out both simple and complex trials in all phases of research. While there are many EDC vendors, some organizations build their own systems in-house. Most EDC systems offer slightly different features, but in general EDC software is designed to streamline data collection.

What are the benefits of an EDC system?

Many research organizations are realizing the advantages of EDC over other methods and are leveraging new technologies to support clinical trials. An EDC system can help you achieve success in the following ways:

Quicker Access to Data. An EDC system can save a significant amount of time with real-time access to data and less time spent on query management. This also saves time at the end of a study, allowing quicker availability of the data for analysis. While it can take substantial time to initially learn how to use a specific system, some are so intuitive that only a few hours of training is required.

Data Security. An EDC system is hosted online with data entry completed on a web-based interface. Given the nature of the data collected in an EDC system, software vendors make sure the data is protected and backed up. Because each user account has designated permissions, most actions can only be carried out by certain roles.

Accuracy. EDC systems improve data quality. There are options to add constraints on a form that prevent inaccurate or illogical values from being entered. Using a computerized system enables legible entries and automatic calculations for cleaner data.

Organization. The use of an EDC system increases the efficiency of clinical trials due to its user-friendly navigation. Search options allow you to easily find and filter exactly what you need and store everything in one location with greater visibility while using less paper.

Cost-Effectiveness. Financially speaking, the cost of an EDC system ranges from free to expensive. Pricing varies, and some vendors charge for additional service and other fees. Purchasing an EDC system can seem like a large investment, but it should save money in the long run.

Compliance. An EDC must be compliant with regulatory requirements. A big one is 21 CFR Part 11. The software should have technical controls in place to ensure data integrity. To properly maintain an EDC system, standard operating procedures (SOPs) are essential to ensuring regulatory and organizational policies are met.

What are the common features of an EDC system?

Most software vendors are continually developing new enhancements to keep up with changes in the industry. While the bells and whistles vary from system to system, there is some functionality that you’ll find in just about every EDC solution.

eCRF Designer. When creating eCRFs, there are design options to choose from that are meant to imitate paper forms. Forms are saved in a library and are often used across multiple protocols. This eliminates the need to recreate commonly used forms and promotes data standards. When building forms, edit checks can be programmed to help prevent invalid data from being entered. This ensures the values entered meet certain requirements.

Data Entry. After a protocol is set up in the system, the data collected is entered into the appropriate forms.

Query Management. An EDC system provides streamlined communication between monitors, data managers, and coordinators. Most systems have auto-generated queries and the ability to manually add queries. All queries need to be responded to and resolved by different roles before the data can be locked.

Data Export. Once you’re ready to pull the data out of the system, there are easily accessible exports to extract patient data. Some systems have built-in metrics reporting that offers insights into the progress of a study.

Electronic data capture systems have become a very popular tool to use in managing data in clinical trials. An EDC system can help increase efficiency, ensure data quality, reduce the time and cost of clinical trials, and help meet regulatory compliance. Learn more about Advarra EDC.

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