For almost a decade, the FDA guidance on humanitarian use devices (HUDs) dated July 8, 2010 has been the go-to document for industry, FDA staff, clinicians/users, and IRBs to understand how to apply the regulations at 21 CFR 814.100, which govern the approval, use, and review of HUDs. Since then, amendments to the HUD program have been made by a variety of federal actions, and FDA produced draft guidance documents to accommodate the changing regulatory and industry landscape. However none were final until September 6, 2019, when the FDA produced Humanitarian Device Exemption (HDE) Program: Guidance for Industry and Food and Drug Administration Staff, which supersedes the July 8, 2010, version.

The new 2019 guidance encompasses both the cumulative amendments made to the program in the interim and a few new ones, including:

  1. Allows for use of HUDs in emergency situations without IRB approval.
  2. Allows HUDs indicated for use in pediatric patients or in pediatric subpopulations to be sold for profit, with certain restrictions.
  3. Increased the maximum number of patients affected by the disease or condition that a HUD is designed to treat or diagnose from 4,000 to 8,000 individuals annually.
  4. Removed the requirement that reviewing IRBs be local.
  5. Allows for the use of an “appropriate local committee” (ALC) in place of an IRB for local review.

At First Glance

An initial scan of the guidance reveals it to be fundamentally different in format from its predecessor: instead of an informal 30-page Q&A, the current guidance uses formal numbered sections and extends to 57 pages. The added content favors industry and FDA staff rather than IRBs and user facilities; that said, it does serve IRBs well in addressing the changes imposed by the 21st Century Cures Act specific to the new role for “appropriate local committees.” More about that later.

The new guidance especially assists industry by providing specific instructions on how to prepare the HDE application and a clear explanation of how the FDA determines probable benefit. Extensive instructions are provided regarding required submission elements, along with a detailed description of FDA review actions for the HDE application. The new guidance also includes thorough, helpful forms and worksheets designed for the FDA staff. Taken together, these updates provide great transparency into the HDE application and approval process.

A separate guidance document entitled Guidance for Industry and Food and Drug Administration Staff: Humanitarian Use Device (HUD) Designations describes clearly how the Office of Orphan Products Development determines that a device qualifies as an HUD. For example, it explains how the 8,000 threshold use is confirmed, how the assertion of a rare disease or condition is verified, and what kind of documentation is required for these determinations.

A Shifting IRB Role?

The original mandate found at 814.124 requiring review and oversight of the HUD by a duly constituted IRB is not negated by the guidance. However, it provides a shared or delegated model of review route by allowing an “appropriate local committee” (ALC) to assume or share these responsibilities. This may benefit organizations, such as small community health centers, that would like to employ HUDs but don’t have a local IRB to directly approve use. Since the regulations require that certain uses (emergency or off label-use) must be reported to the IRB, the need for an IRB to provide oversight is not negated—but it may be provided by a central IRB which in turn can delegate oversight of HUD use to the ALC.

The ALC is defined as a standing committee at the facility that has expertise and experience in reviewing and making treatment decisions for clinical care, and it should include physicians with experience in the treatment of rare diseases or conditions. It also recommends that the ALC include a senior level executive medical staff or faculty member. “Appropriate” is further defined as being free of any conflicts of interest. According to the guidance, a peer review committee, credentialing committee, or Quality Care Committee may fit the bill. Like an IRB, the ALC should have written policies and procedures relating to review and approval of HUDs and should have the relevant expertise represented. A webinar hosted by CDRH on October 21, 2019, fielded questions regarding the relationship between the IRB and ALC, making it clear that the IRB oversight mandated by 814.124 remains in place and admitting that further clarification is needed regarding the relationship of the IRB and ALC.

The nature of review, either by IRB or ALC, is unchanged. The materials to be reviewed, the focus of the review, and the criteria for approval remain the same. The regulatory basis for approval is also unchanged. Unfortunately, the appendix in the previous guidance, which provided a decision tree for IRB review, is gone. Initial review must occur at a convened meeting, and while an IRB may conduct initial review, it can defer continuing review to the ALC. It is clear that review by this committee requires the same familiarity with regulations that was previously the IRB’s sole concern.

Subtle but significant changes are also contained in section VII (C) “Information To Patients.” After reiterating the fact that the regulations do not require informed consent in the use of HUDs, the guidance refers to the selective use of a “written document” rather than a written “informed consent” to provide information to patients. The content of this document is as previously described in 2010, including a list of required elements. Additionally, whereas the 2010 guidance stated that the “patient should always receive” any published information documents from the HDE holder, the current guidance is not so direct; it leaves their use up to the discretion of the IRB or ALC.

Safety Reporting

As directed under the 2010 guidance, adverse events are reported in keeping with the medical device reporting requirements found at 21 CFR 803. Device manufacturers and user facilities must submit these reports to the FDA and IRB/ALC. Annual reports from the HDE holder may be submitted to the ALC or IRB at their request. Guidance for emergency use and off-label use remain very similar.

What’s Behind the Changes?

Without access to the regulators’ minds and thinking, one can only speculate on what prompted these changes. Historically, IRBs have struggled to understand the distinction between HUDs and investigational device exemptions (IDEs) and their respective oversight. Both this latest document and the 2010 guidance emphasize that the primary difference is that HUDs are approved devices, while IDEs are investigational. Nevertheless, HUDs are often treated more like IDEs, resulting in the IRB asking the clinician using the HUD for details applicable to research, such as: who is the PI, where is the protocol, and to whom will you report SAEs/UAP?  In the use of HUDs outside of research, none of these apply. Allowing the ALC mechanism for review and oversight may serve to emphasize this distinction between HUDs and IDEs. Of course, the investigational use of HUDs remains under the sole purview of IRBs.

What Do I Do Now?

In summary, the new guidance looks different from the previous guidance, but the content is very similar. With the exception of the increase in uses to 8,000 and the provision to use ALCs, other changes appear minor; the source regulation remains in place and holds sway. There will no doubt be many requests for clarification from the FDA on the role of ALCs and their relationship to IRBs.

For all stakeholders in the HUD process, the first order of business is to update your regulatory guidance files with the new guidance. (You will find that if you do an online search for the previous 2010 guidance, it will not appear.) IRBs may want to retain the decision tree for review of HUDs found in the 2010 guidance, as it does not appear in—and is not contradicted by—the new guidance. HDE manufacturers will find the worksheets in the new guidance very helpful even though they are designed for FDA staff/reviewers.

Next, update your SOPs to reflect the new guidance. If your institution plans to take advantage of the new ALC mechanism, a new SOP will be required to govern their activity, and it would be wise to include a clear description of roles and division of duties between the IRB and ALC. Any change in policy should be reflected in related internal forms, and finally, training should be scheduled to update all stakeholders.

The recording, transcript, and slides for the aforementioned CDRH webinar on the new guidance are accessible online. This presentation is a great place to start for those charged with managing HUDs in any setting.

Need more information on medical devices? Advarra has you covered. We have experience with all categories of device studies, including implantable and portable devices, diagnostic tools, mobile medical devices, human factors testing, and HUD/HDE studies. Check out our blog Reporting to the IRB: Unanticipated Device Effects (UADEs) in Medical Device Studies or contact us for specialized support.

Social media has emerged as a valuable tool for diverse stakeholders across the research community. Participants and patient advocacy groups frequently use online social tools to identify clinical trial opportunities and provide information and support for each other. Because of this, sponsors and sites have likewise turned to social media to drive their recruitment efforts. The reach of this medium is well-documented, with significant (and still increasing) usage across nearly all demographics according to a Pew survey.  As a result, the use of social media in research will likely continue to expand.

With promise, however, comes challenge. In recent years social media platforms have been subjected to a wide array of criticisms, with confidentiality and data sharing emerging as the paramount concerns. This is most evident in the public’s perception of the events surrounding Facebook and Cambridge Analytica (see here for more information). Thus, it is imperative to ensure that research uses of social media conform to shared ethical norms. Since the US regulations and regulatory guidance do not explicitly address the use of social media in research and recruitment, uncertainty endures regarding its appropriate range of use. IRBs, sponsors, and investigators currently share responsibility for adopting ethical norms and best practices around social media use, which protect research participants and promote public trust in sponsors and the research enterprise.

Further analysis and clarification is needed for three areas of social media in particular: (1) the use of social media to identify and recruit individuals into research; (2) the role social media can play in maintaining engagement with enrolled participants and improving retention rates; and (3) the benefits and risks of social media as a communication tool for research participants and advocacy groups.

Recruitment

Social media is now a proven way to identify and recruit participants. Using this tool appropriately requires close attention and consideration to protect privacy and confidentiality. While online social recruitment strategies typically have similarities with more traditional recruitment methods (e.g., posting an ad on Facebook is in many ways like posting an ad on a billboard or bus), social platforms carry inherent privacy and confidentiality risks (Gelinas et al.). One concern is that many users do not know how to effectively manage privacy settings and fail to grasp the extent to which the information they share over the internet will be publicly available (Boyd; Madden et al.). Accidental disclosure of sensitive health information is a serious risk.

Social media recruitment strategies should therefore be sensitive to this dynamic. While the general risks of social media are voluntarily accepted by people who choose to use the platforms, researchers nonetheless have an obligation to minimize the risks and take steps to mitigate them. Researchers should not invite public online disclosures of sensitive information and should not interact with social media users in ways that would let that person’s friends and followers infer that they are a participant or candidate for participation in research. Researchers can do this by, for example, disabling or limiting public-facing posting capabilities on ad pages. Research staff may also make use of private direct messaging functions to interact with individuals who have shown an interest in research participation. A close understanding of the nuances of social platforms is crucial to participant safety and protection.

Retention

One of the most powerful aspects of social media is the ability to seamlessly connect people who may be regionally or continentally restricted. Harnessing this aspect allows clinical staff to foster a culture of inclusion, minimize participant isolation, and improve communication, especially with participants who are at risk of being lost to follow-up. These things can be achieved through online support/community information groups, discussion forums, or a designated study staff member tasked with building an ongoing digital rapport with participants.

Risks and Benefits of Online Participant Communication

While social media has the power to do good, it is important to consider the necessary safety precautions required with its use. Social media use generally thrives from user-generated content, and this aspect can sometimes present risks to participant understanding and scientific integrity. Clinical staff should—as a best practice—regularly monitor the tools that they use in their studies to prevent the following risks:

Undue Influence and Therapeutic Misconception

For example, based on multiple online participant reported outcomes, Participant A decides to stay in a clinical trial because other people they’ve met online say the investigational product has worked for them. Participant A may decide to withhold any reports of serious adverse events they are experiencing because they doesn’t want to be withdrawn from the study. As another example, consider that if Participant A comes to believe they are receiving a placebo, there is a risk they may withdraw from the study early on those grounds.

Study Unblinding

Example: Participant B reveals their symptoms and experience with taking an investigational product in an online discussion forum. Participant C also reveals their experiences in the form, which are different form Participant B’s. A study staff member responds online and accidentally breaks a study blind by identifying who was on treatment and who was on placebo.

By placing safeguards for the types of data shared, monitoring participant comment sections and communicating rules for engagement, clinical staff can minimize the risks associated with social media threatening study integrity.

Conclusion

Social media holds tremendous promise in the research sphere but requires sensitivity to pertinent regulatory and ethical considerations. Sponsors and investigators looking to incorporate social media into their research toolbox should devote themselves to understanding the details of particular platforms and work closely with their IRB to understand and apply the regulatory framework. Such collaboration is needed for the benefits of social media to be realized in ways that honor relevant norms and uphold public trust.

Need help assessing whether your social media recruitment campaign is in compliance or appropriate for your study population? Advarra can help. Contact us and discuss your study with our experts.

Members of the Advarra team speak at research conferences throughout the year, interacting with folks from both the sponsor side and research administration side of the industry. Recently we spoke with a senior level individual at a leading device manufacturer—we’ll call him “John”—who explained that from his experience, when organizations integrate their research admin functions, it often leads to increased access to new research opportunities, allowing them to build a more expansive research enterprise.

He described a “Tale of Two Health Systems,” one with a centralized research administration and one without. John’s story taught us a few things, and we’re sharing it here in case it helps others in the research community.

As the person responsible for worldwide site selection and study startup, John is always looking for ways to accelerate the process. The faster he and his team get the study up and running, with data quality and patient safety held to the highest standards, the better. What often astounds him is how much organizational and operational ability varies from site to site.

The ability of organizations to efficiently get protocols up and running is enhanced when there is an effective research admin operation.

How Do Sponsors Support Research?

Sponsors do as much as they can to support the startup process, John explained. Their protocols are thoroughly vetted through scientific and operational reviews, with collaboration from advisor sites to minimize mid-study amendments and align protocols with typical clinical visits. By using a single IRB of record (sIRB), sites have a single point of contact and consistent subject protections across the entire study. The sponsor’s contracting office establishes master agreements with sites so they can save time and skip straight to budget negotiation for new protocols.

Despite these efforts, John sees study startup times for large research sites (e.g., health systems and medical centers) vary from as little as 45 days all the way up to 180 days or more. He explained that when sponsors have flexibility, they select the faster sites a lot more often than the not-so-fast sites.

The Tale of Site One

research administration

Qualities of Successful Sites

Our device sponsor colleague has found that successful sites have some commonalities. These organizations make research administration a priority and invest the necessary time and resources to build and maintain a well-oiled research administration machine.

  • First, the various components of their research administration work in unison to conduct feasibility review, contracting, conflict management, IRB… the list goes on.
    • At efficient sites these parts work well together. The research project passes through the various gates and approvals quickly, simultaneously, and without burdening the PI with repetitive or conflicting questions.
  • Faster organizations often outsource a good portion of their research administration functions to commercial groups who do the individual functions much faster (and in most cases just as good or better) than the health system or medical center can do it themselves.
    • Sites can expedite research by relying on the commercial IRB the sponsor has designated and accepting the already approved consent template. They can also have a third party conduct their coverage analysis and budget negotiation (when they don’t just accept the sponsor’s), and some rely on their software vendors to build their EMR billing codes and CTMS calendars.
    • Some sites do just fine with their own internal IRB and resources, but the ones who integrate and outsource are typically faster to study startup.

The Tale of Site Two

research administration

On the other end of the spectrum, John sometimes works with sites that require the PI to work through a myriad of review and feasibility committees operating independent of each other. It can take a week or more to get a confidentiality agreement (CDA) in place if the site will not enter into a master services agreement with the sponsor (which would cover all protocols).

If the site’s budgeting office does not have access to the facility charge masters, the PI must request a budget from each facility or functional group that will provide services under the protocol. Some of those services require committee approval to use the service or facility for research. Eventually a proposed budget emerges, but this doesn’t always line up with the reasonable and necessary charges provided in the sponsor’s template budget. Email storms may ensue as the sponsor attempts to hammer out a budget which keeps changing as new information from the various facilities comes in.

If the site uses a local IRB, it might only meet once every few weeks and may raise questions about the protocol which have already been resolved with the central IRB. Additionally, the local IRB frequently has non-critical consent changes which do not match the consent template language already approved by the central IRB. These changes must go back to the sponsor’s corporate lawyers for vetting, which adds even more time to startup.

When the site’s clinical trials office finally becomes involved, it must build the protocol schedule into the CTMS software (if there even is a central CTMS). This step could have been started at the very beginning of the process and been completed in tandem with IRB review. However, under this inefficient system, the clinical trials office doesn’t get notified of new projects at the site until after they have cleared feasibility and IRB. The research billing codes must also be set up in the EMR by the hospital tech staff alongside more pressing clinical care issues. The result is a startup time of over 180 days. Our colleague says he and his team only use sites like Site Two when they have no other options.

 

And that’s the Tale of Two Sites, as relayed by our sponsor colleague. At Advarra Consulting, we’ve seen similar patterns emerge across the many institutions, health systems, and academic medical centers we’ve supported. Sites that prioritize a harmonious research administration through means like outsourcing, third-party billing and coverage analysis, and relying on a single IRB of record are typically more efficient and easier for sponsors to work with, and they ultimately attract more industry-sponsored research.

At Advarra we strive to help all parties in the research enterprise to work Altogether Better. From timely IRB and IBC reviews, expert consulting to integrate and streamline research administration, detailed and region specific coverage analysis for sponsors and sites, to award-winning clinical trial management software. To learn more about how Advarra can advance your research, contact us.

Many clinical trial protocols include plans to compensate participants for their contribution to the research. According to FDA’s information sheet Payment and Reimbursement to Research Subjects, participant payment is a recruitment incentive and “is not considered a benefit that would be part of the weighing of benefits or risks.” Additionally, in its Informed Consent FAQs OHRP states that “remuneration to subjects may include compensation for risks associated with their participation in research and that compensation may be an acceptable motive for agreeing to participate in research.”

IRBs are tasked with reviewing the amount of payment, as well as the method and timing of disbursement, to ensure that the payment plan does not present potential undue influence. Participant compensation is often a complicated matter, so in this blog I’ll attempt to clarify some issues by shedding light on what an IRB considers during its review.

Definitions

Bear in mind that compensation is not the same as reimbursement. Consider the following definitions:

Compensation
Payment to subjects for participating in a study. It may be considered a recruitment incentive or a way of acknowledging the time and burdens imposed on subjects. Compensation plans require IRB review for assessment of whether they present any undue influence.

Reimbursement
Re-payment for actual costs accrued by the subject while participating in the study (e.g., parking, transportation, mileage reimbursement, childcare, etc). This often requires the submission of receipts. Reimbursement does not generally raise the same concerns as compensation regarding undue influence since participants are being “paid back” money they have spent.

Compensation should be based on time invested and inconvenience. It may also be based on types of risks and procedures. However, compensation should not be considered a way of offsetting risks. The term undue influence is critical here; according to OHRP, undue influence “often occurs through an offer of an excessive or inappropriate reward or other overture in order to obtain compliance.”

IRB Review of Participant Compensation

IRB review should focus on whether the payment plan may compromise a participant’s evaluation of the risks or may affect the voluntariness of his or her decision to enroll and/or to remain in the study. Such concerns may arise, for instance, where an excessive and inappropriate amount of money is offered to participants.

When the research targets economically disadvantaged participants, payment proposals are typically subject to a higher level of IRB scrutiny. Payment may be more important for those to whom it will make a significant financial difference, so this participant population may be more susceptible to undue influence. On a similar note, for studies that enroll minors as participants, the IRB will want to know whether the compensation is intended for the parent/guardian, the minor participant, or both. When providing compensation to minor participants, the IRB will consider what is age-appropriate: for instance, gift cards may be appropriate for older children, while toys/gifts may be more appropriate for younger children.

Notably, the regulations do not define standard compensation limits. Because IRBs are tasked with evaluating compensation plans without defined regulatory standards, many IRBs have developed internal standards to provide for consistency in reviewing compensation.  It is important to understand your reviewing IRB’s standards and provide a rationale for your proposed plan.

Considerations When Developing a Compensation Plan

As mentioned earlier, each IRB maintains its own policies on participant compensation, so it’s important to know what is and is not permissible according to the study’s IRB of record. With that in mind, here are some general considerations for researchers developing a compensation plan:

In determining the amount of compensation to provide, take into account the amount of time each visit takes and the procedures to be performed at each visit. For instance, it may be appropriate to compensate participants a higher amount for study visits that require them to stay in the clinic overnight. Outside of the study visits, it may also be appropriate to compensate participants if they will be expected to complete detailed and time-consuming activities such as lengthy survey or study diary entries.

Credit for payment should generally be prorated, accruing as the study progresses, and payment should not be contingent on maintaining compliance over the course of the entire study. The reason for this is that withholding payment until completion of the study may adversely impact a subject’s right to withdraw from the study at any time. Payment may not always need to be exactly evenly prorated among study visits, but the overall plan should be assessed for potential undue influence. A completion bonus may be permissible as long as it is not so large that it unduly induces participants to stay in the study when they would otherwise have withdrawn. IRBs may have different policies for how large completion bonuses may be, based on, for instance, a percentage of the overall compensation.

Note that small incremental increases in compensation are not necessarily an indicator of potential undue influence and may be acceptable. Additionally, large differences may be acceptable if more involved and burdensome procedures are performed later in the study. Let’s look at a couple examples:

  • In a study where all study visits include similar procedures and risks, a researcher proposes paying $100 for visit 1, $200 for visit 2, $300 for visit 3, and $1000 for the final visit.
    • An IRB might consider this unacceptable, as it could unduly influence subjects not to withdraw from the study.
  • In a study where later visits include more burdensome procedures, a researcher proposes paying $50 for visit 1, where only a blood draw is done, and $300 for visit 5, where a biopsy is performed.
    • An IRB may accept this proposal, as the compensation increase is commensurate with the increased invasiveness and burden of the visit 5 study procedure.

When developing any potential compensation plan, always measure it against the potential for undue influence and how it may impact a potential participant’s voluntariness and willingness to participate in the research.

If you have specific questions about your compensation plans for an upcoming study, contact Business Development or your Coordinator.

 

 

Informed consent is an ongoing process to ensure the participant has an initial and ongoing understanding of the research and its risks. The participant must also sign the informed consent form (ICF), indicating his/her understanding of the research and its risks prior to the researchers initiating any study-related activities; this includes conducting procedures solely for the purpose of determining a potential participant’s eligibility for research participation, with the exception of procedures that would be done anyway for standard clinical practice.

In this blog, we’ll take a look at a unique type of ICF known as the study-specific screening consent. Note that these are different from the general screening protocols and consents often used in Phase I research. In Phase I, this is often referred to as “pre-screening,” and the pre-screening consent is not specific to a particular study.

Often, consent for screening procedures is incorporated into the main study ICF. This kind of inclusive single ICF is generally the IRB’s preference. However, situations may arise where a separate ICF for screening procedures is necessary or more appropriate. For example, if the study is very complicated and described in an already lengthy ICF, it may be simpler to have a separate screening consent to only assess whether an individual is an appropriate candidate for the research study. The main ICF would subsequently place all of the attention on the actual research study.

While screening consent forms may have a somewhat limited purpose, they are still considered consent forms as defined by the regulations. As such, they should include all of the required elements of informed consent. See 21 CFR 50.25 and 45 CFR 46.116 for details on these requirements.

FDA provides some helpful guidance on screening tests prior to study enrollment. According to this guidance, the IRB should receive a written outline of the screening procedures to be followed. The screening consent should focus on describing the study screening procedures. Complete details about the main study do not generally need to be included in the screening consent. However, a brief summary of the main study must be included so that participants understand the procedures they will undergo if they are screened into the study. This summary helps explain to potential participants why the screening procedures are being performed, so they can make an informed decision about whether to agree to the screening procedures.

Need help drafting content for your screening consent? Here are a few examples from Advarra’s IRB guidance:

Benefits Section

Participating in the screening procedures will determine whether you are eligible for the study. There is no other direct benefit to you from participating in the screening procedures. If these procedures show that you are eligible and you are considering participating in the main study, then a comprehensive review of the experimental procedures, risks, and potential benefits of the main study will be discussed with you at that time.

Alternatives Section

The only alternative to participating in the screening procedures is not to participate. If the procedures show that you are eligible and you are considering participating in the study, alternatives to participating in the study will be discussed with you at that time.

Still not sure how to proceed with a screening consent? Contact Business Development for support.

It’s not always easy for research teams to determine whether a project should be defined as quality improvement (QI) or if it truly is research involving human subjects. I recently discussed this confusion with some colleagues, and I’ve shared highlights from that conversation in this blog post. I hope this helps shed some light on this common challenge.

Let’s start with the basic definitions:

  • Research defined by the federal regulations is a systematic investigation designed to develop or contribute to generalizable knowledge.
  • Quality improvement is generally deemed to be a systematic process that involves data activities designed to bring about immediate improvements to healthcare delivery in a particular setting.

In research, the question we’re trying to answer is usually some version of “does this work?” or “is this better than other approaches?” The question is relatively narrow and straightforward. In quality improvement, we have a variety of activities that look quite different but all fall under the umbrella of quality improvement. QI can be practical problem solving, addressing an issue within a single hospital or unit like whether nightly bed checks at regular intervals reduce patients falls. Or it can be broader in scope, such as implementing an established intervention and then collecting data to evaluate whether it improves care. In general, quality improvement does not seek to create generalizable knowledge; rather, it evaluates programs specific to a particular organizational setting.

When determining whether a project is research or quality improvement, consider whether you’re seeking an answer that will contribute to generalizable knowledge—or whether you’re trying to improve practice in your local setting by implementing a practical solution to a problem or evaluating something that is already considered an established practice.

Risk and Research

If the project involves randomization, it’s usually research, as randomization implies that an answer is not already known. Randomization is also a potential risk to study participants, and generally, there is no risk involved in quality improvement activities.

When you start looking at identifiable participant data, you cross the line into research. Even if you’re only recording de-identifiable data, you initially have to go into a database to look at identifiers, and this can increase risk to human participants.

Exempt from IRB Review

The regulations outline specific requirements for research to be exempt from IRB review. This is different from quality improvement not requiring IRB review, because QI is by definition not research. If it is quality improvement, it does not require IRB review.

This can get tricky, however, if you want to publish the findings of your quality improvement project. Many publications ask about IRB review prior to accepting an article. In this situation, I suggest you be clear with the publisher that this is not research and avoid using the word “research” in describing the QI project. You might say something like, “This is not research but rather a quality improvement program designed to assess a standing program in our clinic.”

Note that the IRB has no input on whether a project has to be published. Additionally, intent to publish does not in and of itself turn a QI project into research.

 

Still not sure if it’s quality improvement or research? Contact the Advarra team for assistance.

In the course of caring for patients, a physician has a lightbulb moment: maybe it’s an epiphany about a medical device that could be adapted for a new clinical indication, or an inspiration to explore the possibilities of a commercially available drug used for a new purpose in patient care. In any case, the great idea comes down to a research question that can only be answered by a classic controlled clinical trial. How hard could that be? 

We covered the basics of investigator-initiated trials in Beginner’s Guide to Investigator-Initiated Trials. Now we will focus on the challenges hindering successful completion.  

Inadequate Support 

The range of settings in which a clinical investigator may undertake an investigator-initiated trial (IIT) is broad and may be the determining factor for success. A clinician in an academic medical center with resources available to assist in protocol and writing, statistical planning, funding sources, and study execution certainly has a great advantage over the individual clinician with fewer or none of these. It is essential then to survey the resources available before beginning and engage them at the outset, before the protocol is written. It is this IRB professional’s observation that IIT protocols often reflect great ideas but not much more. And a poorly written protocol is a signal of poor support rather than lack of good intent.  

A frequently tapped source of support is the pharmaceutical/medical device industry; virtually every major pharmaceutical and device company has a dedicated investigator-sponsored research assistance program. They are happy to engage the medical community and its physician investigators, as it offers a rich source of “real world evidence” they seek outside the traditional investigational device exemption (IDE) and investigational new drug (IND) route. Recent regulatory changes have also made it possible for companies to expand product indications outside the traditional routes. Industry support also includes essentials such as assisting in protocol writing and statistical support. Though it offers a solution, a level of independence is sacrificed as these companies typically demand in return specific terms regarding publication rights and claims to new products or processes.   

Inadequate Design 

No matter how well intended or written a protocol is, all is in vain if it is insufficiently powered to validate the study endpoints and answer the research question. Likewise, all is lost if the study is not practically carried out in a reasonable time, even if the statistical plan is sound and able to reach robust conclusions. This may explain why some study results never get published; there is simply nothing to show. For an IIT to succeed, it is essential to engage knowledgeable and experienced researchers to provide a “second set of eyes” and review research proposals to assure their soundness and feasibility. 

Inadequate Funding 

Clinical research is expensive, especially if it is undertaken in a way to produce valid scientific results. It requires physical resources such as facilities and clinical venues, testing capabilities like imaging and labs, and specialized personnel. Industry often fills this gap, but even generous industry support does not compare to Phase I-III industry–sponsored studies. This usually means doing much more with less. This explains why most investigators who venture into IITs add it to an already robust and well-supported and funded industry– or agency–funded research program.   

Funding is an important issue, not only because of resource needs to conduct the study, but also because of legal and compliance risks associated with where the funds originate. It’s essential to tread carefully when seeking funding from industry sponsors. The HHS Office of Inspector General (OIG) has entered into several high-profile, multi-million dollar settlements with pharmaceutical and device manufacturers resulting from anti-kickback penalties related to sham clinical trials. Most settlements resulted in fines as well as corporate integrity agreements to assure compliance. 

Industry support differs in many ways, usually in the form of funding, provision of product, or aid in study design and conduct. Other sources include cooperative groups, nonprofit research organizations or networks, or the sponsor-investigator’s own healthcare institution. If industry provides support, the issues of intellectual property, data ownership, and publication rights become sensitive, especially for academic institutions. Industry funders will insist on a robust contract, laying out these terms in detail. Sponsor-investigators will also want to assure liability concerns (indemnification, subject injury, etc.) are also addressed. Industry sponsors also have varied approval processes that might include legal/regulatory, biostatistics, and safety review. Regardless of the funding source, a well-funded project is essential to successful completion.  

Regulatory Burden 

The regulations governing human research originate from two main sources in the US: 

  • The Common Rule and its participating agencies governed by DHHS with rules published in 45 CFR 46, and 
  • The FDA governed by the rules found in 21 CFR 312 (drugs) and 21 CFR 812 (devices) 

Compliance with the Common Rule is imposed when the HHS or its agencies provide funding. In addition, compliance with the FDA rules is imposed when using FDA regulated products in research. If neither of these apply, the institution conducting the research will impose its own rules via IRB standard operating procedures (SOPs), which may also elect to impose the Common Rule to any research conducted within its walls. Rules governing human subjects protections and IRBs originate from the Office of Human Research Protections and are published in 21 CFR 50 and 56, respectively.  

These rules translate into a regulatory burden placed on the clinical investigators, and varies based on funding source and investigational article, if any. The regulations governing FDA–related products are often the most challenging for the investigator/sponsor to meet. If a clinician seeks to use an FDA–regulated drug or device outside its approved indication it may need an IND (drug) or IDE (device) to allow its use in an investigation. Since filing an IND or IDE require submission of all available manufacturing, safety and existing clinical data, it is wise to start down this pathway with the cooperation of the original IDE/IND holder so the data may be cross referenced by the agency from existing IND/IDEs. Monitoring and safety reporting requirements are critical and become exponentially burdensome if an investigator/sponsor seeks to mount a multisite study with colleagues in his field. DHHS funded research is currently bound by the single IRB mandate, but FDA regulated research may be conducted at multiple sites, each with their own IRB. As stated in Beginner’s Guide to Investigator-Initiated Trials, FDA regulated research requires the sponsor/investigator to comply with all relevant requirements.

Challenges for IRBs 

From an IRB perspective, the most common challenges are incomplete, scientifically inadequate, or underpowered studies. A primary concern of the IRB is risk versus benefit. Often, benefits include or are limited to benefitting others or society from the knowledge gained. If a study is not scientifically sound or unlikely to complete, this benefit is lost. As a result, IRB review cycles are often protracted due to the need for multiple requests for modifications to assure scientific soundness. 

The IRB must also determine or validate the regulatory status of any regulated product included in the study. Medical devices require IRB review to determine significant risk or non-significant risk status. However, the device may be an exception from the IDE regulatory requirements if it is being used as labeled in the study—but this is not always a straightforward determination. Likewise with FDA regulated drugs, these may be exempt from IND requirements if they are used as labeled, or if the study is not intended to support a marketing application for change of label or for use in product marketing. Again, the answers to these questions are not always easy to discern. 

Putting It Together 

It’s clear, for all the reasons mentioned above, succeeding in investigator-initiated research takes determination and dedication. However, because the research originates from the clinician’s own inquiring mind, the level of satisfaction can be very high. 

Interested in starting an investigator-initiated study? Get in touch with us here or send an email to businessdevelopment@advarra.com. 

The potential use of stem cells for the treatment of human disease finds its roots in the 1961 when two scientists, Drs. James Till and Ernest McColluch serendipitously found that the intravenous injection of bone marrow cells in mice previously treated with radiation led to the growth and proliferation of cells in the spleen of the animals, leading to the clinical application of bone marrow transplant.  Since then, use of peripheral blood or bone marrow have built a long history in the medical community, especially in the oncology space.  Much academic research has also been done on using pluripotent stem cells for a variety of potential applications.

Most recently, we’ve seen the proliferation of “regenerative” medicine uses for stem cells derived from adult, amniotic, fat-derived bone marrow and other tissues.  According to a study published in August of 2016, there were already 351 US businesses engaged in direct-to-consumer marketing of stem cell therapies in 570 clinics, no doubt a fraction of the number today.  Due to the regulatory framework that has lagged behind this trend, many raise alarm that these represent expensive, unproven, scientifically dubious treatments being marketed as cures for a wide variety of diseases and disorders.

The Regulatory Landscape

When regenerative stem cell products began to be developed, these products derived from human donors initially followed regulations designed to protect the public from transmissible disease (Public Health Service [PHS] Act Sections 351 and 361).

In 2005, FDA exerted regulatory oversight of human cell, tissues and tissue-based products (HCT/Ps) that are minimally manipulated and intended for homologous use only (21 CFR 1271). The manufacture of these products must not involve the combination of cells or tissues with another article and must not have a systemic effect unless designated for autologous transplantation, first- or second-degree-related allogenic transplantation, or reproductive use. These products do not require pre-market approval and initially included tissues such as corneas and heart valves.  Any tissue products outside of these parameters is subject to the familiar requirements for pre-market approval of drugs, biologics, and devices.

The limits of “minimally manipulated” and “homologous use” have been tested by the introduction and use of regenerative stem cell therapies, such as mesenchymal tissues which are removed, processed, and reinfused/injected into the patient. The FDA responded with a guidance document in November 2017 that clarifies “minimal manipulation” and “homologous use.” This guidance also revealed that many of the products previously assumed to qualify for these characteristics in fact do not, and are thus subject to premarket regulations governing drugs, biologics and devices.

Additionally, an exception found in 21 CFR 1271.15(b) which includes “an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same procedure” was applied by product manufacturers to regenerative stem cell therapies. However, FDA’s guidance clarified that many of the products being sold and used under this exception do not actually qualify and are thus subject to pre-market approval requirements.

The 21st Century Cures Act of 2016 established the Regenerative Medicine Advanced Therapy (RMAT) designation for cell and tissue products, though the RMAT criteria admittedly encompass only a fraction of the regenerative stem cell therapies. And though this pathway provides a potentially less burdensome and expensive approval process, of the 97 RMAT applications received since December 2016, only 31 have been granted, while 53 were denied.

The sheer volume of potentially noncompliant products and their uses has become so great that the FDA granted a 3 year “discretionary enforcement” period that ends in December 2020. During this period, all manufacturers of these products are expected to re-evaluate their products in light of the guidance and re-justify their classification.

Exerting Oversight

In the meantime, a gap in guidance and oversight to assist those developing and employing HCT/P products has developed in the landscape of regenerative stem cell therapies. As reports of serious injuries related to the use of stem cell products mounts, state governments, professional governance organizations, and others have stepped in to bring order to the scene.

  • The Federation of State Medical Boards created a Workgroup to Study Regenerative and Stem Cell Therapy Practices which resulted in the adoption and publication of a policy on Regenerative and Stem Cell Therapy Practices in April of 2018.
  • The International Society for Stem Cell Research (ISSR), in existence since 2002, published a series of articles and guidances to advise clinicians, researchers and IRBs on the conduct of clinical trials to assure the ethical and scientifically responsible use of these products.
  • State governments have also stepped in to protect the public from what was seen to represent unproven, risky and costly treatments. To date, laws have been enacted in California, Washington, Florida, Texas, and others that impose controls over the use of these products.

Discretionary Enforcement

The “grace period” offered by the FDA in its discretionary enforcement statement did not indicate that the federal agencies would leave the public and medical community unprotected and uniformed. In addition to the guidances previously mentioned, successive FDA commissioners Robert Califf, MD, and Scott Gottlieb, MD, published articles in the New England Journal of Medicine in March of 2017 and March of 2018 respectively. Dr. Califf’s article focused on the unproven nature of many of these products and warned of the risks related to their use. He also assured the medical community that the FDA would address the challenges related to these products and provide guidelines for their development and pathway for approval. Dr. Gottlieb’s article clearly laid out the current regulatory construct imposed on these products and proposed a pathway to assure that these therapies are safe and effective. The FDA has also issued warnings to the public advising them of the “illegal and potentially harmful” stem cell treatment offered by “dishonest and unscrupulous stem cell clinics”.

Addressing the Bad Actors

The FDA and FTC have both stepped in to crack down on the more egregious offenders in this scene. The FDA has issued 483s and warning letters to stem cell clinics finding that their products do not meet the criteria of “minimally manipulated” and exception under “same surgical procedure” criteria. They also fault clinics on good manufacturing practices. In October of 2018, the FTC imposed a $3.31 million judgment against a California-based physician and his stem cell clinics which also mandates refunds to consumers harmed by “the defendants’ allegedly deceptive conduct”. These events can only be perceived as a taste of what is to come as the agencies bring the situation under control.

The Challenge to Physicians, Institutions, and IRBs

The tenuous situation surrounding stem cell therapies presents many challenges for institutions, physicians, and IRBs. During this period of uncertainty and risk, institutions balk at permitting their clinicians to pursue the use of these products, while consumers, convinced of their worth by abundant but anecdotal “evidence” clamor for access, even at great expense. Clinicians interested in safe and ethical use of these products are stymied by the costs and regulatory burden of pursuing approval within the premarket approval process. Stem cell product manufacturers, already profiting from the sale of their products during this period of “discretionary enforcement,” will soon be scrambling to meet the regulatory criteria for continued distribution and sale of their products with the December 2020 deadline fast approaching.

Where Do We Go From Here?

All of the players in this landscape agree on one thing: valid clinical safety and effectiveness data is essential for continued safe and ethical use. All are aware of the huge expense and burden of mounting phase I-III clinical trials common to the drug industry and are paralyzed into inaction. In the 2018 NEJM article, Marks and Gottleib propose a novel and possibly workable approach: encourage individual or small groups of physicians to collaborate in the development of regenerative stem cell products for use in each respective clinic under one Biologics License Application (BLA). They also propose the use of “real-world data” in support of such BLAs. The proposal calls upon IRBs to assure that any clinical research done in pursuit of approval for these products are ethical and scientifically sound. Fortunately, the International Society for Stem Cell Research advice for IRBs offers a comprehensive framework for the review of stem cell trials.

And then there are the research practitioners, each of us in our various roles in the medical and clinical research community who are often identified by family and friends as the one who can advise and guide them through this labyrinth. The grandmother or aunt who reads the anecdotal reports on social media claiming dramatic cures for arthritis or other problems common to aging.  The niece or nephew who learns of a dire diagnosis and in their desperate internet search finds a clinic in a distant location offering treatments and cures using stem cells.  Each of these ready to take on great, out-of-pocket expense for what is likely untested treatment.  If nothing else, being well informed will serve us best.

Surveys can be incredibly useful in the clinical research operations arena to help measure process improvement among stakeholders. But before diving in, it is important to brush up on the basics and best practices of survey creation.

Define the Objective

To start the process of creating a survey, it’s necessary to define the objective. Think about the following questions before putting together your survey: What question are you trying to answer? What topic are you trying to address? Define your objective by thinking: “By the time I finish this survey, I want to know X about Y.”

Some examples of survey objectives pertaining to process improvement in clinical research might include:

  • Staff satisfaction with particular processes
  • Determining where gaps/roadblocks are in the study activation process
  • Most effective ways to provide ongoing training in a particular area
  • Feedback on the implementation of new processes (pre-implementation and/or post-implementation)

Define the Outcome

Define what outcome you are hoping to reach with the data you will collect from this survey. What are you really trying to measure? For example, with the survey you may hope to measure satisfaction level, agreement level, competency level, effective training types, etc.

Define the Audience

From whom are you interested in obtaining responses? To whom does this topic apply? Create a list of audience attributes to help define your intended audience and aid in question creation.

For example, a survey about what types of training should be implemented for your research staff would be applicable to all research staff regardless of years of experience, both participant facing or not, and managers and individual contributors. An example of when you would need to narrow down the audience would be training questions that only apply to newer employees because they address onboarding.

Topic Development

When coming up with the topic for your survey, it is best practice to start with a general topic. What areas describe the objective? Keep in mind nuances and anticipated differences based on respondent demographics, respondent activity, categories of the objective and situational differences.

Question Development

Within each topic you have created, write down as many questions you can come up with to capture all aspects of each topic. Try to phrase questions in a common way to avoid confusion and think about the answers that accompany each question.

If possible, stick with a single scale to keep respondents from having to think too hard about the format of the responses and instead focus on the content. Types of scales include sliding scales that incorporate frequency and percentages, visual acuity scales, Likert scales, and free text answers. If you choose to include free text responses, consider how you will analyze and interpret them, as this can be a very manual process.

Neutral responses are another factor to keep in mind while developing questions. Do you include a “Neutral,” “No opinion,” “Neither agree/disagree” response in your survey? Oftentimes neutral responses don’t result in actionable data, so many survey designers choose to omit this option to force respondents to choose a side.

When reviewing the content, make sure there are NO double-barreled questions. If the respondent could answer two ways, then your question is double-barreled. Figure out what you really want to ask in that question and if there are two aspects to measure, ask two questions. Also make sure you are not asking leading questions. For example, “The outdated procedures do not cover training opportunities” could be turned into “The procedures do not cover training opportunities” to remove the leading portion of the statement.

Once you draft the questions, review them. Stick with the topic and if the question does not address your original objective, get rid of it. If questions overlap, determine the best wording and remove the extra question. If the questions are intended to address different items, figure out how to word the question to represent the desired difference. Finally ask “what am I missing?” and add questions as needed.

Minimize the number of questions needed to achieve the ability to measure the objective. Respondents are less likely to finish the questions at the end if the survey is too long, so be mindful of the order in which you place questions, giving priority to the questions to which you’re most interested in seeing the answers. Put questions in an order that makes sense because good flow helps with obtaining complete and accurate survey results.

Collecting Demographics

Think carefully about what demographics are needed in your survey. Are there any desired sub-analyses? Like the questions, only ask demographics needed for the analysis. Also consider elements about your respondents that help provide explanations and associations with results.

Collecting Responses

Determine the most effective method to distribute and collect responses (paper, email, web-based, etc.) How long should you keep the survey open? Reminders to participate can be helpful to get higher participation levels but not so many that it becomes a nuisance.

Analyzing Results

Data cleaning includes collecting all the data in a single location (making sure to save the original data in case of mistakes) and translating to a standard format that can be analyzed. The more time spent on ensuring your data is clean, the quicker and more accurate the analysis will be. Spend time understanding the data you receive especially if you have free-text responses. Determine how you would like to handle missing data (leave blank or fill in with another value). Follow an analysis plan consisting of descriptive statistics (frequencies, median/mode response) and or assessing differences (categorical and numerical).

The Advarra team (formerly Chesapeake IRB and Schulman IRB) continues 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.

The following FAQ expands upon previous FAQs we’ve published and provides additional insight into the integration process. We’ve also assembled a central list of all integration updates we’ve published so you can easily find any updates you might have missed.

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. If you don’t see your question addressed here, please contact your Study Coordinator or Study Manager, or email us.

Operational Impact FAQ

1. What is the methodology of the corporate integration?

The integration methodology, which has been successfully employed previously in 4 IRB and 1 IBC integrations, focuses on people, process and technology to ensure that the best practices of both organizations are captured and institutionalized.

By ensuring our people are actively involved in SOP harmonization activities and are well trained prior to and after the integration go-live date, we allow our teams to dedicate their efforts to maintaining the high level of quality and customer service that characterized both of our legacy organizations. We also provide robust training and personal support for our clients, which is augmented by dedicated Client Service Coordinators and Study Managers, to ensure a seamless client experience.

Our highly trained staff and managers review and update all SOPs to ensure we emerge with an enhanced set of policies that not only capture the best practices of both organizations but are also consistent with the needs of our clients.

Our proven technology is a key component in implementing our enhanced SOPs in a timely and consistent manner that enables us to quickly leverage best practices across our entire enterprise. Our cloud-based, 21 CFR Part 11 compliant IRB platform allows clients to easily view study documentation and interact with our staff to resolve any issues in a timely and collaborative manner.

2. How does Advarra plan to harmonize SOPs that the staff and IRB will follow?

Core SOPs and IRB policies are currently undergoing harmonization. Following an extensive and comprehensive gap analysis, current legacy Chesapeake SOPs are being used as the foundation to create harmonized and enhanced Advarra policies and procedures. By utilizing legacy Chesapeake SOPs as the foundation for Advarra’s SOPs, we are able to greatly expedite the integration process since they already capture procedures required for the use of the cloud-based CIRBI platform. Enhancement of the platform, which is the cloud-based system that Advarra will implement, is currently underway and is based on best practices from both legacy organizations.

3. When will the Advarra SOPs be finalized for the legacy Schulman/Chesapeake teams to work under?

Advarra SOPs will be finalized prior to the May 1, 2018, implementation date to allow adequate time for training Advarra staff and IRB members.

4. How will you ensure all staff are trained prior to May 1, 2018?

Advarra’s dedicated Quality Assurance Team will manage and track all staff and IRB member training. All Advarra SOPs will be finalized and all staff will be trained at least 2 weeks prior to implementation, scheduled for May 1, 2018.  

5. What will happen to legacy Schulman/Chesapeake SOPs?

All legacy SOPs will be retired and retained for reference.

6. For studies that were initiated under the legacy SOPs, will the new Advarra SOPs govern?

Yes, new Advarra SOPs will govern current active studies. However, there is little impact to client submission/reporting requirements since both legacy organizations are AAHRPP accredited and have similar policies and procedures governing client reporting requirements. Any changes impacting studies will be communicated prior to May 1, 2018.

7. How are internal operational processes being harmonized? What other processes are being harmonized?

Several internal working groups meet on a consistent basis to evaluate every policy, SOP, IRB reviewer form, submission SmartForm, etc. to harmonize all policies and procedures across the Advarra organization. The Institutional Official and Director of IRB Reviews (a position created specifically for this reason), along with other Advarra representatives, are meeting regularly to ensure consistency across all 10 IRB panels.

Other processes being harmonized include quality control, quality management, other IT platforms/systems and internal communication/escalation.

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

As indicated in our 1572 Note to File that was sent to our current client base, 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 has indicated that clients should email gcp.questions@fda.hhs.gov with any further questions or confirmation regarding 1572 updates.

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

9. Will Advarra use the existing CIRBI forms, or have the forms been updated to merge legacy Schulman and Chesapeake forms?

There will be one set of submission SmartForms for Advarra. The legacy Schulman and legacy Chesapeake forms have been merged into the new Advarra CIRBI SmartForms, which encompass the combination of information collected by both legacy Chesapeake and Schulman IRBs.

10. How will the merger impact an institution’s FWA? Do we need to reapply or update our FWA?

As with 1572s, an institution’s FWA will not require an update. Please reference the Contractual FAQ below and the 1572 Note to File for more information.

11. I had a dedicated Study Manager at Schulman and a dedicated Client Service Coordinator at Chesapeake. Who will be my primary Point of Contact at Advarra?

Advarra will work with each client to identify the best dedicated point of contact for their unique research portfolio going forward. We understand that while some clients may prefer a dedicated “service team,” others may prefer a primary point of contact that they currently work with at each legacy organization. We strive to provide the approach that works best for your organization. If you have questions or preferences, please contact Business Development to discuss.

12. I haven’t received any updates on the merger to date. How does Advarra ensure its customers are getting information about the merger?

Advarra is committed to communication and transparency regarding our merger and ongoing integration. We have distributed a number of merger-related email announcements and have also posted FAQ documents and other updates (such as the recent Note to File related to 1572s) on our legacy websites. These messages have also been shared via our social media accounts and through direct outreach by Advarra staff members.

If you are a current customer who has not received these email updates, we recommend you add news@advarra.com to your safe email sender list. If you are not a current customer and you wish to receive updates, you can sign up here or contact Business Development for further support.

You can access a complete list of all integration communications to date here.

IRB Structure FAQ

1. How will you ensure the processes between the IRBs are harmonized?

Advarra has a strong regulatory organizational structure in place to ensure streamlining, consistency and harmonization between all of our IRBs. These activities are overseen by the Chief Compliance Officer and the Executive IRB Chair, as well as the Director of Regulatory Affairs and the Director of IRB Reviews. In addition, all IRB reviews will be conducted under harmonized Advarra policies and procedures.

2. How were IRB members harmonized between the legacy IRBs, related to IRB member recruiting and qualification?

All legacy Schulman and legacy Chesapeake IRB members have appropriate expertise to serve as IRB members with Advarra and are appropriately qualified and trained to serve as IRB members. Going forward, the training of new Advarra IRB members will be standardized, combining the training materials used by both legacy organizations.

3. How many IRB meetings will be conducted per week?

Legacy Schulman held 5 regularly scheduled meetings a week; legacy Chesapeake also held 5 regularly scheduled meetings as well as 2 Canadian meetings a week. Going forward, Advarra will have 10 US and 2 Canadian IRB meetings per week. Some of these meetings will be comprised of specialized panels focused on device, Phase I, oncology and neurology research. With over 100 IRB members in the US and Canada, Advarra is able to accommodate rapid review timelines for all major therapeutic areas, research phases and other specialty areas.

5. Are IRB membership rosters available?

Updated IRB rosters will be available by April 27, 2018.

6. How will Advarra ensure transparency regarding which IRB reviews studies and where submissions are routed?

Advarra will be operating as a completely integrated company with 1 IRB in the US and 2 REBs in Canada. All reviews will be done by Advarra. All submissions will be made through a single platform, the Advarra Center for IRB Intelligence (CIRBI) Platform, and all communications and approvals will be through that same system. This fully integrated approach will provide a seamless, transparent experience to customers and help ensure consistent, quality reviews.

Technology FAQ

1. What is the methodology for merging legacy Schulman studies into CIRBI?

From 2015 through 2017, we developed a validated and flexible comprehensive import capability for the CIRBI platform to support 5 successful earlier integration projects. This capability has been fine-tuned and further improved with each successive data migration.

In preparation for migration to CIRBI, we have reviewed and imported the entire dataset housed in the legacy Schulman eTools system. All data in the CIRBI dataset is compared and reconciled with the data from the original database.

All data extracted from the legacy Schulman eTools system is staged in a validation environment using the same import tool. This allows us to validate the data and ensure that data integrity is maintained.

Because of the large volume of studies and studies to be migrated, we have identified weekly migration tasks, referred to as “sprints.” Each sprint is defined with a set of studies for a given client and associated sites for those studies. By defining the scope of the sprint, it allows us to work with groups of customers to establish a plan, discuss timelines and expectations and provide access and training to customers for CIRBI use.

2. How will sites get access to the CIRBI platform and what training will be provided?

Sites that are not currently registered in the CIRBI platform will be notified prior to Advarra registering each user on his/her behalf. Registration will occur as studies are being prepared for migration into the CIRBI platform. A large number of sites have been working with both organizations prior to the merger.

While the platform was designed to be very user-friendly, training will be provided to sites by request (both initially and ongoing) or through pre-scheduled webinars requested by sponsors/CROs. You will be notified if a webinar is scheduled by the sponsor/CRO on your behalf.

3. Will there be access to the legacy Schulman eTools for closed studies or items that are not migrating over?

All study documentation, either for closed studies that have not met the retention period or for documentation that will not be imported into the CIRBI platform, will be available to clients in eTools.

All historic documents for active or terminated studies that are currently available through eTools will remain in place through the document retention period (terminated date plus 3 years).

4. Is there a time that the legacy Schulman eTools will no longer be available, and if so, what is the plan for the documents stored there?

Documents stored in eTools will remain available until a given study is closed and the regulatory retention period has ended (terminated date plus 3 years).

5. How has the legacy Schulman staff been trained on CIRBI, and how has this been documented?

A significant number of IRB members and Advarra staff have already been trained and are working within the CIRBI platform, and the remaining IRB members and staff will receive training in April 2018. Training is documented in records maintained by our Quality Assurance Team.

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 Advarra Consulting (legacy 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.

5. What is the structure of the Advarra Corporate Leadership Team?

  • Pat Donnelly, Chief Executive Officer
  • Jeff Wendel, President and Chief Operating Officer
  • Scott Uebele, Chief Financial Officer
  • Randall Hein, President, Advarra Consulting
  • Robann Cunningham, Senior Vice President, Business Development
  • Michele Russell-Einhorn, Chief Compliance Officer and Institutional Officer
  • Lauri Carlile, Vice President, Operations
  • Nitin Uplekar, Chief Information Officer

For more information, please reference this news item.

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 the Accounting Team. 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 the Accounting Team.

3. Will clients with Advarra contracts have a single point of payment for all invoices (both from legacy 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 Business Development.

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 the Contracts Team.

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 Schulman IRB to Advarra, Inc. You will receive communication directly from Advarra’s Contracts Team. Questions regarding contract status should be sent to the Contracts Team.

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

IRB Services will be updating its name to Advarra as well. Contracts with IRB Services remain valid; however, Advarra’s Contracts Team will be issuing amendments to current MSAs to indicate the name change/assignment from IRB Services to Advarra, Inc. You will receive communication directly from Advarra’s Contracts Team. Questions regarding contract status should be sent to the Contracts Team.

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

Falcon Consulting Group, Inc. has changed its legal name to Advarra Consulting, Inc. This will not affect the validity of these contracts. The Advarra Contracts Team has provided our clients with a legal notice of name change. There is no action required by current clients. Questions regarding contract status should be sent to the Contracts Team.

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

Provision contracts will be assigned to Advarra Consulting Inc. The Advarra Contracts Team has notified Provision clients regarding the assignment of contracts. Questions regarding contract status should be sent to the Contracts Team.

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 (IRB00000971) 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.

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 d/b/a for the entity to whom they were submitted.

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)
  • Advarra Consulting Inc. (formerly known as Falcon Consulting Group Inc.)
  • Provision Consulting

Clinical research continues to grow throughout the world, with researchers looking outside the US for new and diverse subject populations to help develop and improve investigational therapies. Requirements for research ethics review vary considerably country to country, and the regulatory variety can be daunting for a researcher new to working outside the purview of US regulatory agency requirements.

While it’s not possible to cover the many unique regulatory requirements of each nation in a single blog, I will discuss the basics of ex-US research ethics review for US-based researchers. For those seeking information on a particular country’s clinical research requirements, the International Compilation of Human Research Standards compiled by HHS is a good place to start.

Review by a Non-Local Ethics Committee

In many parts of the world, research ethics review is conducted locally by institutionally based ethics committees. Some countries may require additional layers of review at the local and/or national level, and most nations do not permit oversight by ethics committees that are not based in that country. Centralized research ethics review, like the US central IRB model where a single committee oversees research at multiple sites, is not common outside of North America.

There are some exceptions: for example, Canadian research regulations share similarities with US regulations and permit centralized non-Canadian research ethics committees to oversee some research, provided certain requirements are met (like including a majority of Canadian citizens as committee members).

Check with the country’s research ethics agency and/or the local institution to understand what is and isn’t possible. When non-local oversight is not permitted, researchers must work with local regulatory agencies and research ethics committees to ensure they comply with all local requirements.

How Can a US-Based IRB Help with Ex-US Research?

Research ethics committees do not exist in all countries, and when there are research ethics review requirements, not all local committees are alike. In some cases, it may be helpful to provide the local committee with a US-based IRB’s study review summary. While the regulations may not be the same, the perspective of a US-based ethics committee may be a helpful resource for the local committee’s own review deliberations. The ethical standards applied by the US-based ethics committee should be no less stringent than they would be for research conducted in the US.

Some ex-US research ethics committees may also accept dual oversight, where both the local ethics committee and the US-based ethics committee review the study and maintain oversight as the regulations permit. This may be an option for studies with sites in the US as well as in another country. Dual oversight may not work in every scenario, so check with the research ethics committee of record to understand what is possible.

Contact an Expert

Navigating a new set of regulatory requirements can be tricky, to say the least. Language and cultural barriers can exacerbate an already complicated situation. If you’re new to conducting research outside of the US, it may be beneficial to contact an expert for support. Some consulting groups and CROs may have resources based in the ex-US country who can help navigate the local requirements and processes.

Need auditing or quality support for an international study? Contact our consulting team.

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