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Regulations for research involving devices, in vitro diagnostics (IVDs), and digital therapeutics differ from those governing pharmaceutical development. While drugs require Phase I-III clinical trials—and are also subject to post-approval tracking—digital therapeutics, devices, and IVDs may be able to leverage bench testing, animal studies, pilot studies, and training sets. These are usually followed by validation studies, pivotal trials, literature reviews, and even real-world evidence studies, depending on the individual product’s intended purpose and the risk level.

Medical devices, IVDs, and digital therapeutics have the potential to bring significant health benefits to patients of every age group, including healthy populations and those with varying severity of health ailments and disease burdens. Interpreting evolving regulations for these devices is often a unique challenge for emerging biotech companies. Staying on top of evolving regulatory requirements for a complex medical device category can be overwhelming, even for well-established life science companies.

How do you determine if clinical trials are needed for your device? Here are some ways to decide if clinical trials are necessary and navigate the compliance intricacies of a complex medical device category.

Function Dictates Regulation

It’s essential to understand how the product interacts with a patient, as well as what level of importance it holds to the patient’s health. In other words, what are the risks and benefits of the product? The greater the risk, the more likely a series of trials for market clearance or approval will be required.

In the United States, a medical device, IVD, or digital therapeutic is categorized as one of the following:

Class 1: Non-invasive, low risk to the patient, and subject only to “general controls” around registration, branding, and labeling.
Class 2: Products posing a higher risk to the patient; most products in this category require a 501(k) premarket notification, meaning a detailed comparison to a device already in market.
Class 3: Applied to products with the highest risk, or to Class 2 products that are the first in their category. These products will require clinical trial data to get to market, but with significantly fewer participants required as compared to a drug trial.

Intended Use, Indication, and Mode of Action

Intended use and indication for use are often confused or thought of as the same. Think of the intent or purpose for the intended use (e.g., what the device does) and the indication for use is the patient population, disease, condition, and duration of use. Additionally, consider intended users and the environment of use. These claims are those made on the product labeling, and they need to be successfully demonstrated in the clinical evidence.

Consider three examples to determine your path: a tiny camera the patient swallows to take internal photos, a new blood test designed to indicate monkeypox, or a mobile device application monitoring a patient’s A1C levels.

The indication follows the intended use, but it also places the product in the context of a disease/medical condition. It’s important to bear in mind the indication can change the product’s risk level. In the example above, the camera diagnoses intestinal disorders, the blood test diagnoses suspected infection, and the mobile medical app (MMA) supports patients with diabetes types 1 and 2.

Finally, what is the product’s mechanism of action or mode of action (MoA), especially as it relates to patient interactions? Thinking about whether the product is invasive, non-invasive, significant, or non-significant risk, and how it operates inside or outside of the patient is crucial. This is how the product achieves its therapeutic effect. For instance, a harmonic scalpel vibrates as it cuts, a COVID-19 test detects SARS-CoV-2 antibodies by measuring antigens in a person’s saliva/mucus, and a digital therapeutic program electronically signals how or when a patient should adhere to best practices or adopt a positive-reinforced behavior.

Gather and Publish the Evidence

A comprehensive clinical evidence generation plan determines what critical data is needed as evidence indicating the product does what it is supposed to do safely. Some markets – specifically the EU – may require publication to obtain product approval.

Most critical is understanding what kind of study to conduct. To find this answer, return to the type of product and its risk level to determine if a trial is required, and if so, what kind. Types of trials include:

Pilot or feasibility: small study to collect safety results, proves a concept and can guide future study design
Verification studies (training set): smaller studies designed to test a device or train an algorithm prior to design freeze
Validation studies: larger studies designed to support the efficacy and safety – or sensitivity and specificity – of certain devices and/or algorithms claimed
Demonstration of Equivalence: EU distinction for literature and other comparative evidence against an existing product’s performance
In silico: Studies designed to simulate data without testing in humans
Pivotal: Large, statistically driven study to confirm efficacy, safety, and risk-benefit
Real-world evidence (RWE): Data is collected from real-world sources, including registries, electronic health records, administrative claims, etc.
Post-market safety: usually in support of obligations after clearance or approval
Human factors: to inform ease of use, features, labeling, and instructions by end users

Stay focused on the future of the product after approval, when indications for other conditions may be added or the design of the product is adjusted. Approval may be the immediate goal, but it is likely not the product’s final goal.

The implementation of the single institutional review board (sIRB) model has gained significant traction in recent years, particularly with mandates from federal regulatory agencies such as the National Institutes of Health (NIH) and the Office for Human Research Protections (OHRP). While this shift aims to streamline multi-site research, it has also introduced new complexities for institutions and IRBs.

A Brief History of Single IRB

Historically, IRB systems were decentralized, with each institution conducting its own ethics review for research involving human subjects. This system worked well when research was largely conducted within a single site. However, the rise of multi-site research in the 1990s and early 2000s highlighted inefficiencies in this model, as institutions conducting the same study were subjected to multiple, sometimes conflicting, IRB reviews.

In response, the NIH implemented a policy in 2018 mandating the use of an sIRB of record for all multi-site studies. This model was later incorporated into the revised Common Rule by OHRP in 2018. The goal was to reduce administrative burden, streamline study startup times, and enhance the efficiency of clinical trials without compromising ethical oversight.

How Single IRB Works

The single IRB model designates one IRB as the “IRB of record” responsible for overseeing the study for all participating institutions. This IRB is charged with ensuring compliance with federal regulations, while the other institutions, known as relying institutions, contribute through a local context review. This local review ensures site-specific policies, state laws, and community standards are considered.

The reliance process involves documentation between the IRB of record and the relying institutions, usually through reliance agreements like those provided by the SMART IRB platform. These agreements outline each institution’s responsibilities, reducing the need for negotiating individual agreements for each study. However, institutions must still undergo local reviews for issues such as radiation safety, pharmacy reviews, and other ancillary concerns.

Challenges in Implementation

While the sIRB model offers many potential efficiencies, institutions face several challenges during its implementation. One major challenge is navigating local context reviews. Although these reviews are not full IRB reviews, they still require the submission of materials to ensure site-specific policies and procedures are followed. This additional step can slow down the process, especially in institutions with less robust research infrastructures.

Moreover, establishing reliance agreements between the IRB of record and relying institutions can be time-consuming. Institutions may use agreements like SMART IRB, but not all sites are signed onto these platforms. In such cases, institutions need to draft and negotiate individualized agreements, which can further delay the process.

In addition to reliance agreements, many institutions are still learning how to effectively streamline the local context review process. The onboarding process for sIRB reliance can take longer than study teams expect, leading to frustration and delays in starting clinical trials.

Optimizing the sIRB Process

To make the sIRB model more efficient, institutions need to adopt established, clear reliance processes early. By using platforms like SMART IRB, which offer a master reliance agreement and other resources, institutions can streamline the reliance process and reduce time spent on negotiations. SMART IRB’s single sign-on approach allows institutions to bypass lengthy agreement reviews, as all parties agree to the same terms from the outset.

Institutions can also benefit from creating clear workflows for local context reviews. Using tools like two-part consent forms is key, which separate general study information from site-specific details such as HIPAA language and local contact information. This allows local institutions to review only the sections relevant to them, speeding up the process without compromising compliance or ethical review.

Another key to success is communication. Clear communication between the IRB of record and relying institutions is of utmost importance, particularly when managing expectations around timelines.

Regulatory Developments

The regulatory landscape for sIRB is continuing to evolve. In September 2023, the FDA published a draft rule proposing the expansion of the sIRB mandate to studies regulated by the FDA. Public comments are still being collected, but if the rule is implemented, it will mark a significant step toward harmonizing IRB requirements across federal agencies.

Moreover, OHRP’s recent draft guidance on sIRB addresses questions about local legal considerations, including how IRBs of record should handle state and local laws. Although the guidance is not yet finalized, it provides valuable insight into the role of sIRB in navigating local legal issues. A central resource or database of state laws can benefit institutions, helping them better understand legal requirements potentially impacting their IRB determinations.

While the sIRB model offers a more efficient framework for multi-site research, its implementation requires careful planning, clear communication, and a robust understanding of both local and federal regulations. Institutions investing in streamlined processes and leveraging tools like SMART IRB will be better positioned to overcome the challenges and fully realize the benefits of sIRB.

As federal mandates expand and guidance continues to evolve, institutions must remain flexible, adjusting their processes to ensure compliance while maintaining the highest standards of ethical review. By doing so, they can ensure the shift to single IRB not only reduces administrative burden but also enhances the integrity and efficiency of clinical research.

How do you know your experimental therapy is working? Sometimes, it can be as simple to determine as comparing drug A to placebo and measuring the physiological result with an approved assay. But what does “working” really mean when efficacy means something subjective, like quality of life, reduced psychiatric events, or less symptoms?

In most cases, the results you are really looking for and trying to prove in a trial can be complex. How do you strategically plan your therapy and research objectives to improve the chances you will satisfy what the regulators are looking for and ultimately get your therapy approved for marketing? Can you use surrogate endpoints, multiple endpoints, what statistical power will you need, will diversity play a factor in planning your research strategy? All key questions to consider and address before the therapy even leaves the lab.

One area receiving increased focus from the Food and Drug Administration (FDA) are trial designs incorporating multiple endpoints to support efficacy. FDA recently released guidance on how sponsors can approach multiple endpoints in their clinical trial design in a way which will likely satisfy the regulators when it comes time for marketing approval. This latest guidance also suggests and reenforces the need for an independent review of clinical events to establish unbiased verification of the endpoint, as outlined in the agency’s 2006 guidance. Similar guidance has been issued from the European Medicines Agency (EMA).

Why Issue New Guidance?

Therapies are increasingly complex – innovative cell and gene therapies, immunotherapies, and even traditional small molecule drugs are interacting with the human body in more advanced, multi-factored ways.

When trying to demonstrate a therapy’s efficacy with potentially multiple complex modes of interacting with the human body’s cellular functions, sponsors naturally will include multiple endpoints to highlight and maximize the positive impacts of the therapy.

In the new guidance, FDA alludes sponsors are increasingly including multiple endpoints in their trial designs presented to the agency. That the agency felt it was necessary to issue guidance on this specific topic implies there have been problems with multiple endpoint designs. These problems likely lead to delays in study startup and regulatory approval of innovative new therapies.

When utilizing multiple endpoints to demonstrate potential efficacy of a new therapy, the recognized challenge is the trial designs require increasingly complex statistical methods to account for multi-variant and confounding variables.

FDA is concerned these increased statistical complexities in a trial may increase the “likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints … if there is no appropriate adjustment for multiplicity.” In short, FDA is acknowledging this is complex area, so make sure all clinical development and biostatistical experts are well-versed on how to design these types of trials to ensure startup and/or regulatory approval is not delayed.

Approaching Multiple, Complex Endpoint Designs

The task of developing protocols containing multiple endpoints is not impossible, but it needs to be appropriately thought out and integrated into the trial’s endpoint and statistical design.

Determining the appropriate endpoints, and how best to measure them, is the first step. Sponsors need to carefully consider how they will prove safety and efficacy in a manner sufficient to satisfy the regulators. FDA is concerned that “failure to account for multiplicity when there are several endpoints evaluated in a study can increase the chance of false conclusions regarding the effects of the drug.” With that in mind, sponsors incorporating multiple endpoints in a trial must rigorously evaluate how to account for the array of endpoints potentially interacting or interfering with each other in such a way as to mask the true safety and efficacy of the therapy.

In addition to having multiple primary endpoints, when evaluating the appropriate endpoint design for a trial, sponsors need to additionally consider the use of composite endpoints, co-primary endpoints, and multi-component endpoints. All of these depend on the nature of the disease condition and the modality of treatment interaction.

Endpoint designs are as unique and varied as the disease conditions and therapies themselves. Developing the endpoint design and overall approach of a clinical trial program is mostly science, but there is a bit of art to it as well.

Working with Statisticians

FDA’s guidance highlights a number of statistical designs potentially suitable to account for multiplicity, including:

The Bonferroni Method
The Holm Procedure
The Hochberg Procedure
Prospective Alpha Allocation Scheme (PAAS)
The Fixed-Sequence Method

The sponsor’s biostatistical team and the independent data safety monitoring board (DSMB) statisticians should be well versed in these statistical methods. These groups are equipped to ensure the appropriate method is selected and detect safety issues within the data, so participants are appropriately protected.

Engaging an Independent Endpoint Adjudication Committee (EAC)

With complex and multivariant endpoints comes an increased need for medical experts to carefully scrutinize the clinical events and determine if the endpoint(s) have been met. Typically, an independently administered EAC handles this evaluation. Also known as a clinical event committee (CEC), EAC members evaluate a clinical event in the context of the protocol and the individual participant’s medical information. There are usually three or more reviewers who evaluate the dossier and determine whether the event meets the endpoint.

An EAC’s determinations are incorporated into the overall trial data. As experience and data is accumulated, the statistical model begins to be satisfied. Eventually, an evaluation by the independent DSMB of accumulated data is completed to verify there are no emerging safety or futility issues.

The Importance of an Independent EAC for Regulatory Approval

The core role of an EAC is to have medical experts independently evaluate a clinical event to determine if a defined endpoint or clinical threshold has been met, or if the event should be categorized in some way (e.g., caused by the study drug or by an underlying condition). Such work requires medical judgment and a lot of associated information to make the determination. This is particularly important when untangling the complexities of multivariant endpoints.

Both FDA and EMA stress in their guidances the importance of the EAC evaluators being independent of those sponsoring or conducting the research. Using an independent EAC provides assurance to the regulators the endpoint determinations have been carefully evaluated by multiple experts without the impression of bias.

What to do When Developing Clinical Trials

FDA is clearly concerned about this topic – thus the need to issue guidance. Sponsors should take note and ensure their trials utilizing multiple endpoint designs have appropriate statistical designs to account for multiplicity.

Study the statistical methods, plan the trials, and talk with experts and FDA early about trial design plans. Do not end up running a trial only to find the endpoint design, or the associated independent EAC/DSMB plans, are not adequate to satisfy the regulatory agency.

Bottom line: Designing a clinical trial approach and program is complex. You can do a lot of things in a trial; it’s mostly science and part art. FDA is watching this area of trial design, so if you are planning a trial with multiple endpoints, be certain you have the right clinical and statistical experts as part of your team.

Medicare coverage analysis (MCA) is a systemic process of developing a billing plan for a clinical research study. Also known as coverage analysis, MCA provides an in-depth analysis of how all the items and services listed in the clinical research protocol are billed per guidelines provided by the federal agencies.

The Centers for Medicare and Medicaid Services (CMS) provides information and guidelines to determine whether billable items and services to be billed to the third party (insurance/patients) as routine cost or will be paid by the sponsor as a research-related procedure. Since 2000, Medicare has covered the cost of the routine care for the Medicare beneficiaries who are enrolled in qualifying clinical research studies. Effective January 2022, Clinical Treatment Act requires all U.S. states and territories to cover the cost of routine care for the Medicaid beneficiaries who are participating in a qualifying research study.

Advantages of Having an MCA

Developing a billing plan by performing MCA will help both the individual research site and sponsor estimate their expenses on protocol-required items and services. Clinical research studies enrolling human subjects also need to adhere to the approved MCA-generated billing plan if routine services are billed to the patient or their insurance. If not, sites enrolling the human subjects may face serious consequences, including federal lawsuits, financial penalties, and/or the ban of CMS coverage for the applicable institution or investigator. Additionally, by performing an MCA, research participants are assured of the financial liability (payments and copayments for the items and services) while participating in the clinical research.

Performing an MCA

The first step in considering what items and services are covered by insurance is first determining whether the clinical trial is eligible for coverage. The National Coverage Determination (NCD) 310.1 for Routine Costs in Clinical Trials outlines the requirements for clinical trials to be deemed eligible for coverage.

If the study is determined to be a qualifying clinical trial, each potentially billable item or service listed in the protocol should be analyzed to determine coverage. NCD 310.1 outlines coverage routes available for items or services provided in absence of a clinical trial (e.g., conventional care), performed to monitor known human side effects of an investigational agent, and/or considered reasonable and necessary for the management of the patient’s underlying condition. Further support can be obtained in referencing peer-reviewed treatment guidelines approved by Medicare.

Please note, service-specific NCDs and local coverage determinations (LCDs) may further affect coverage. Service-specific NCDs and LCDs should be prioritized when determining coverage, as any limitations noted will trump support found in peer-reviewed guidelines mentioned above.

It is also important to note coverage must remain consistent across the entire patient population. As per NCD 310.1 and ethical standards, no costs should differ between two patients entering the same clinical trial. If an assessment is determined to be routine care for one patient but solely research-related for another, the assessment in both patients should be covered by the sponsor conducting the clinical trial. This is yet another key benefit of performing an MCA, where potentially hidden costs are identified prior to budget execution.

A highly valuable tool for research staff, electronic consent (eConsent) can simplify the consenting process for both staff and participants. Used effectively, eConsent can increase consenting quality while reducing audit findings at sites. As the industry continues to shift from studies conducted exclusively in person to more convenient hybrid formats, eConsent can be very useful.

When organizations begin to implement an eConsent platform, there are various things to consider to ensure a seamless implementation process.

Understand Organizational Requirements

Before implementing a specific eConsent tool, it may be helpful to understand how this can directly affect not only your organization, but other review committees as well. Specifically, you will need to consult your independent review board (IRB) as you use this platform for informed consent purposes.

Depending on the individual IRB, processes may differ. For example, some IRBs may not require approval of a specific eConsent system, but rather, rely on an attestation stating the eConsent is aligned with the approved consent. In other cases, some IRBs may review the system one time, and any subsequent protocols on the same system are fine. However, other IRBs may want more detailed documentation and screenshots.

In order to effectively understand your organization’s processes, the best thing you can do is speak directly with your IRB. They are there to help you and are willing to answer any questions you may have to ensure a seamless review.

Consider Participant Population

Equally important as organizational requirements, sites must consider their participant population and if the process they are using is effectively serving them. The right process will depend on the type of study conducted; a low risk study has a different process compared to a high risk study. There are also additional factors of the participant population staff need to consider, such as:

Learning styles
Access to email
Access to a clinic
Language

Finding an eConsent platform to support multiple options in regard to language, location, or learning styles is key to ensuring a seamless user experience for participants. Thoughtfully implementing an eConsent platform tailored to your participant population can improve your organization’s patient centricity and help participant-study retention.

Thoroughly Set up the eConsent Platform

Before staff teams begin to use the eConsent system, it must be successfully implemented so they can effectively use it. Investing in the platform’s configuration setup up front will save staff headaches in the future. It gives staff a chance to become confident with the platform prior to a study, and when they work with participants to navigate the platform, it makes it easier for participants to understand what they are using. The more staff understand how to navigate the system, the easier it will be for them to teach participants, which also saves participants time as they use it.

As staff are going through the setup process, it’s helpful to know the way they can configure the eConsent system to streamline the consenting process. eConsent allows staff to configure various requirements, such as signatures, initials, or checkboxes. Additionally, it allows staff to build “rules” or “required fields” around document signatures. This enables coordinators to complete their tasks and necessary signatures (and completing them themselves).

Conduct a Mock Visit

With everything set up in the consent platform, to test everything out, sites may want to consider conducting a mock visit. This is a great way to test the workflows for both participants and staff. Mock visits can be helpful for both remote and in person consenting processes.

While a mock visit is helpful for many reasons, it’s particularly beneficial as research staff are getting ready to use it with trial participants. For many patients, this will be the first time they use a platform to consent, rather than setting up an appointment to go into a clinic to walk through it with a coordinator. They will only be confident using the system if staff are knowledgeable and thorough in explaining how it works. Conducting a mock visit will enable staff to see eConsent from the patient’s viewpoint, understand what they see as they use the platform, and this will help staff better explain the tool as patients navigate it.

Mock visits are also beneficial for staff. Doing a test-run of the platform helps ensure everyone is on the same page and coordinated within the system. Encouraging staff to test out the system helps them see where sticking points could occur within the system. For example, going through a visit may help staff see if all required initials or signatures are marked, or if one particular section of consent needs to be explained in further detail.

An eConsent platform has the ability to transform how participants understand the study they are a part of, and can make the process easier on sites’ behalf as well. Taking steps like these helps ensure your organization is set up for success well before the first patient successfully uses the platform.

Budget negotiation is an integral part of a clinical trial’s success. Proper clinical trial financing ensures a site’s internal costs are covered, facilitates better negotiation, and leads to more compliant practices. With the per patient cost in clinical trials averaging around $41k, it is critical to begin with an internal budget appropriately capturing the estimated costs. This internal budget can be used as a baseline when working with the sponsor to achieve appropriate funding.

How to Develop an Internal Budget

Before requesting any edits to the sponsor’s budget template, it is recommended for an institution to develop an internal budget. This budget details the estimated costs associated with conducting the clinical trial. The process begins with a thorough review of the coverage analysis completed by the site and study documents provided by the sponsor (i.e., protocol, informed consent, and sponsor budget). The coverage analysis outlines which items and services are billed to insurance and which items are paid for by the study sponsor.

The research items in the analysis then translate into the direct per patient costs within the internal budget. Additional underlying costs include the time and effort from research staff such as the investigator, study coordinator, and data management. Consider other costs, such as:

Administrative fees
Institutional overhead
Unscheduled visits
Screen failures
Ancillary department fees
Drug costs
Patient stipends

Once the internal budget is complete and reviewed for accuracy, it’s time to begin the negotiation.

Best Practices for Budget Negotiation

Prior to contacting the sponsor, redline the sponsor’s proposed budget template to better align with site study costs. Don’t forget to also redline the payment terms commonly found in the clinical trial agreement. It’s important to note negotiations could occur with a contract research organization (CRO) rather than a sponsor. Sponsors may hire a CRO to participate in the negotiation for them and serve as a proxy, similar to Advarra’s role with research institutions.

Regardless of the point of contact, stay consistent and aim for a set negotiation timeline goal. It’s likely there will be several rounds of negotiation with edits required at each counter. In these situations, it’s important to effectively and efficiently communicate. Remain firm on non-negotiable items and maintain flexibility on those items allowing for negotiation. Respond in a timely manner and follow up with the sponsor as needed to keep the timeline on track. Finally, make sure to avoid double billing during negotiations. This occurs when two payments are made for an item or procedure. For instance, the sponsor pays for an item that is also billed to Medicare (as otherwise highlighted in the coverage analysis). This is a major compliance concern and should be avoided at all costs. Once the budget is finalized, the process moves onto the contracts team (if needed) and other study team members for signature routing.

Negotiation Strategies

In a perfect world, sponsors would have unlimited funding for all foreseeable site expenses. However, in lieu of the effect dedicated by an institution, sponsors dedicate just as much time (or more) to properly outline the costs of their clinical trial. If rates fall too low or certain fees are not included, be transparent. Provide reasoning or documentation showing the need for any costs in question. This may include current procedural terminology (CPT) codes relating to specific services, a signed PDF acknowledging the extensive review needed to confirm the expense, or the reallocation of other fees to make up for areas of deficit.

Budget negotiation is an arduous and laborious task with the potential to delay anticipated timelines. Be sure to promptly respond to any sponsor inquiries. If the sponsor has slow response times, follow up with them as needed via email or phone. Institutions facing continued sponsor pushback or delayed timelines should utilize an established internal escalation plan. In the same regard, your institution may encourage the sponsor/CRO to escalate required fees for further review. Through it all, remember to maintain a good relationship with the sponsor. A successful negotiation requires mutual benefit.

Clinical trial site selection can make or break a trial’s success before it even begins. The average cost to open an investigator site is estimated at $50,000¹ – a price point compounding quickly when onboarding multiple sites. When you consider around 11% of sites² fail to even accrue one participant on a given study, cost savings become a major consideration when evaluating which sites to partner with for a trial.

To ensure you’re maximizing the time, resources, and funds associated for each clinical trial, we’ve outlined essential strategies for identifying the appropriate sites, analyzing historical site performance and feasibility, and implementing better communication and tools across stakeholders.

Analyzing Selection Criteria and Site Performance to Identify Your Sites

To identify clinical research sites for a study or trial opportunities, sponsors, contract research organizations (CROs), and sites leverage different datasets. Each sponsor collects data on the trials they’ve conducted and the performance of sites they’ve engaged in the past. A CRO may have more data across more therapeutic areas than a single sponsor. A site has historical performance data of their trials across a variety of sponsors and CROs, along with experience in specific clinical areas.

Each dataset is powerful because there is a lot to learn from past site and trial performance. In which trials have sites achieved their enrollment targets? What is a particular compliance rate with a specific site, or even a particular investigator across different studies? What selection criteria may be inhibiting your trial’s success? And do you have the resources to support sites with less experience in a particular clinical research area, but a strong relationship with a specific pool of patients?

Data like this can help solidify if a site will be a good fit for your unique trial and minimize the risk in your decision. However, each study stakeholder is limited in their decision-making by the dataset informing them. According to our recent trend report, The Current State of Trial Opportunity and Selection, 83% of the polled sites are looking for new trial opportunities, and over half of sponsor and CRO respondents indicated they utilize new-to-them research sites in at least half of their studies.

Factors Influencing Site Selection

Communication is an essential part of any effective clinical research relationship, and it’s important to always engage with each site thoroughly. Even if a particular clinical research site isn’t a fit for your current trial, they may be an important partner in future studies. Building these relationships will help you down the road, and can increase transparency between stakeholders.

There is a bi-directional need for communication. Sites need to feel comfortable being honest and transparent about how they think they’ll perform on a study. And even though they’re working with a lot of sites, sponsors need to allow some flexibility in getting information for the site to highlight why they’re an appropriate site for the study. This conversation gives sites the ability to communicate where their true strengths and weaknesses are.

An open line of communication can help to improve site management and engagement in the long term. The site evaluation process is a learning opportunity for everyone involved, and processes like study feasibility questionnaires (SFQs) can prove useful for all stakeholders involved. Our trend report found sponsor organizations are generally seeking to learn about four key evaluation items when selecting a site:

Experience with patient population
Clinical research experience
Access to patient population
Historical performance of enrollment

An SFQ introduces the opportunity for sites to answer sponsor’s key questions and provide additional information, but low site response rates have contributed to frustration—only about 65% of SFQs sponsors and CROs distribute are completed and returned.³

On the other hand, sites are also frustrated by the lack of feedback. We found 83% of sites want more study opportunities, but rarely receive feedback from sponsors and CROs on why their site was not chosen. The lack of communication doesn’t help to foster site relationships, and missing insight likely contributes to low SFQ response rates.

Leveraging Technology in Site Selection

Technology is absolutely vital to a study, and you need a reliable way to store and collect data. Successful site and sponsor/CRO relationships are better enabled with tools designed to bring more insight to the conversation, while ensuring data is reproducible and properly communicated.

Oftentimes, relationships between sites and sponsors are very protocol-specific. Sponsors and CROs typically rely on an SFQ to gather site information. However, sites do not feel the SFQ allows them to properly highlight their abilities to conduct research. The sponsors rely on the SFQ and if the site doesn’t meet the criteria, they are not considered any longer. In some cases, this is in error as a follow-up conversation about the sponsor’s findings and probe of the site may find they actually are qualified and well suited to take on the study.

Communicating beyond these rigid questionnaires can allow for negotiation opportunities, potentially resulting in a highly successful site and clinical trial partner for a sponsor/CRO. The right tools can ensure mutual success, such as additional training resources, a financial feasibility analysis, and a centralized institutional review board (IRB).

It’s important to remember there is a time frame between selecting and activating a site, during which these tools can be implemented. A typical academic medical center may take up to six months on average to activate a trial, while an independent site may take 30-45 days before enrolling patients.⁴

Another essential step before activation is aligning on standard definitions for operational metrics — establishing common terminology when discussing how activation and trial conduct activities are proceeding. This step will optimize the workflow between all of the trial stakeholders, and can ensure the research is measured with the same set of conditions.

How Advarra can help

At Advarra, we work to advance clinical research through innovative solutions designed to leverage our industry expertise, optimizing your trial all the way from initial research to market.

To streamline site identification for your clinical trial, consider leveraging Advarra SiteIQ. The study planning tool was designed to simplify study startup by identifying suitable sites for your clinical trial using Advarra’s comprehensive database.

References:

Optimizing Clinical Research Operations with Business Analytics, https://support.sas.com/resources/papers/proceedings11/204-2011.pdf
Coalition for Clinical Trials Awareness, http://cctawareness.org/about-us/
Trend Report: The Current State of Trial Opportunity and Selection
JCO Oncology Practice, https://ascopubs.org/doi/full/10.1200/OP.19.00325

Is the clinical research industry winning or failing at innovation? It probably depends on who you ask and likely full of nuance. In the past decade, trials have evolved to include not just traditional drugs and medical devices, but also innovations like cell and gene therapies, wearables, and more. As exciting as that growth may be, it invites more complexity. Despite the fast pace of medical innovation, the lack of consistency between technology systems managing these advancements ultimately inhibits research progress.

As the clinical research industry has evolved, so have the many vendors looking to solve point solutions. While some have legitimate use cases and widespread adoption, the sheer volume have created a new bottleneck to achieving innovation in clinical research. In the funnel of transformative solutions, we see too many solutions stuck in pilot mode after a key case study or two, with few solutions trickling into transformative and driving toward faster treatments.

As sponsors have adopted technology designed to support automation, document management, and data collection, research sites have also continued to grow more sophisticated in their approach to data and operations management. Between the required sponsor platforms and their internal systems, that is a lot of redundancy, duplicative workflows, frustrated staff, and wasted time.

Site staff are spending between 10-20+ hours per week just on data entry into sponsor-provided systems. They indicate at least half of this is duplicate data that is otherwise already tracked in sites’ own systems. Imagine if we declared every Monday “Duplicate Data Entry Day” for all sites everywhere. Has innovation really succeeded in clinical research if this is the state we’re currently in? I believe our industry needs an intervention.

While the numbers above don’t inspire confidence, I believe we are on a path to success, allowing for more innovation and site centricity. The good news is people are talking about the gaps in innovation and site centricity now. Sponsors and sites are more aware and have improved collaboration to address these challenges. More notably, discussion is reversing the pendulum from continued release of more technology solutions, to connecting them to do better with less. Here are a couple of shared ideas, their downfall, and a proposed alternative.

Idea: Commit to single platform solution

Challenge: If there were a single platform vendor across all stakeholders, admittedly it would be easier to communicate and exchange information across all stakeholders. However, like all monopolies, it would extinguish innovation due to lack of competition. The solution is not to consolidate all sponsor tech to a monolith single company. We need new technology and new companies to push the envelope, drive innovation, and think differently to keep us moving forward as an industry.

Idea: Use only site technology instead of sponsor technology

Challenge: Without some sort of standardized data and visibility at the sponsor level, sponsors would not get on board, and it would make their work impossible. The solution is not to completely flip the switch and have sponsors no longer choose any technology and instead log into each site’s technology. By completely pushing to the other end of the spectrum, we add cost and burden to the place where it directly drives up costs for the patient in the end.

How can we Innovate While Reducing the Burden on Sites and Improving Outcomes for Sponsors?

Our answer is to centralize, standardize, and integrate. Centralize sponsor/site collaboration into a single portal and integrate as many touchpoints as possible. Create and use standards wherever we can.

How can we do this? Let me explain.

We need to recognize there are items that need to be consistent on the sponsor side, as well as on the site side. There are many touch points between sponsors and sites, and everything must work together for a trial to be successful. For example, the sponsor needs clinical data in a format consistent across sites to run statistical analysis and drive to expedient FDA approval.

However, does this mean if we want source data directly from the electronic health record (EHR) system, the sponsor chooses the site’s EHR? Of course not. This is where standards become the key to bridging the two sides. Sites have their own systems for source data entry (including, but not limited to, the EHR) and sponsors have their own systems for clinical data such as electronic data capture (EDC), a central clinical data warehouse, etc. CDISC has paved the way for this model through ODM, CDASH, and CDISC standards.

The same process applies, and is more commonly used, for regulatory documents. Sponsors use their own electronic trial master file (eTMF) system across all studies to remain compliant. Sites use their own electronic investigator site file (eISF) system for the same reason. The solution is not for sponsors to require sites to use a sponsor-approved eISF. That is not best practice for the same reason a sponsor wouldn’t use a separate site eTMF for a single part of a study.

Advarra has made headway on this through recent launch of the Secure Document Exchange, driven by the Advarra Site-Sponsor Consortium. CDISC is now working within the consortium to develop standards much in the same way, so we can enable integrations across the board.

We are highly orchestrating these two use cases and working very closely with sites, sponsors, CROs, and CDISC to make the connected research ecosystem a reality, continuously forging our way down this highly collaborative path empowered by integrating both sides of the clinical research spectrum.

When we work collaboratively, there are many more use cases providing opportunities to ease sites burden. Technology integration is key to enable site-centricity at scale.

Though it may not be well known among many industry colleagues from sponsors and CROs, sites invest in their own technology. It’s true – most sites now leverage a clinical trial management system (CTMS) to manage their research operations. These systems, built specifically for sites, help them across their entire research portfolio, regardless of the sponsor. In the past few years, additional site technology has been more widely adopted, including eReg, eSource, televisit capabilities, eConsent, and more. This is important context for why sites are pushing back on using any sponsor-driven tools duplicating these same capabilities but only for a single trial.

Our article, It’s Time for Sites to ‘Bring Your Own Technology’ (BYOT) outlines why site technology is so important for sites.

Now, let’s fast forward a few years (or decades, depending on your level of optimism), and imagine a site has technology they have optimized, trained all of their staff on, and automated across all of their operations. Imagine the site can go to their own technology and see all of the items they need to tackle for all of the studies they are assigned to, watch refresher training videos on protocols and the technologies they use, document protocol or participant progress once and have it automatically sync with sponsor systems, and trigger next steps and downstream billing workflows. Imagine a new innovative technology is developed, and a sponsor wants to use it for new trials. If it’s integrated in with that same site tech platform, the burden is drastically lower on the sites and thus can be rolled out and adopted with key stakeholders (the sites) to maximize the technology’s potential.

To make this a reality, we need to forge a new path of site-centric integrations, standards spanning stakeholders and centralizers of clinical research. We are working hard to enable site-centric integrations at scale through the Advarra Site-Sponsor Consortium and through our API Partner Program. Both are aimed at leveraging existing site technology, and provide value to both sites and sponsors through integrations.

I truly believe if we can integrate with site technology and standardize integrations, we can innovate much faster as an industry. Join us in helping create a better-connected future.

Informed consent is one of the central protections the regulations provide to research subjects. This tip sheet outlines the regulatory requirements for research informed consent forms (ICFs). The regulatory requirements for informed consent will vary depending upon which regulations apply to the conduct of a particular study.

Note: Individual institutional review boards (IRBs) may have their own specific policies regarding how ICFs should be formatted, how to address certain regulatory criteria, and other considerations. Always check with your IRB of record to confirm you understand its requirements.

Part C of the Belmont Report notes that respect for persons requires subjects be given the opportunity to choose what will or will not happen to them. The informed consent plays a key role in this respect and should adhere to three main elements:

Information
- Provide information to help potential subjects understand the study’s risks and benefits to help them decide whether they wish to participate in the research
Comprehension
- Provide information in a way that is meaningful to potential subjects. Investigators should be able to make certain the potential subject truly understands the presented information
Voluntariness
- Consent to participate in research is valid only if given voluntarily. To facilitate this, avoid coercion (i.e., threat of harm) and undue influence (i.e., excessive, improper, and/or inappropriate reward) when informing potential subjects about the study

Language and Reading Level

Ensure the ICF is written in a way that will make sense to the study’s specific subject population. U.S. regulatory agencies recommend written ICFs contain easy-to-read and understandable information so a lay person can make an informed decision about participating in a study.

Generally, the aim is for a sixth to eighth grade reading level; however, it is recognized that some consent forms require technical language which will make this level unreachable. Before proceeding with a specific approach, make sure it is appropriate for your study. Flesh-Kincaid readability tools can help with grade level assessments.

The consent form cannot include any exculpatory language. Exculpatory language is that which has the general effect of waiving or appearing to waive a subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability from negligence. The Food and Drug Administration (FDA) website has guidance titled Exculpatory Language in Informed Consent, which includes examples.

If you are targeting a community that includes a sizable number of non-English speakers: Have translated ICFs available when English is not a potential subject’s first language. Whenever possible, have translated ICFs available ahead of time so you don’t have to wait to have the consent conversation with a potential subject.

Should an unexpected non-English speaking subject arrive before a translated study ICF is available, the regulations permit providing an oral presentation of the informed consent information along with a short form consent document and a written summary of the oral presentation. To access Advarra’s translated short forms in over 20 languages, login to the Advarra CIRBI Platform and select “Reference Materials.”

If your study will enroll children younger than the legal age of majority in your area: Consider whether assent documents are appropriate (in addition to the standard ICF) and/or whether it may be suitable to add an assent signature line to the standard ICF. Most IRBs identify age ranges when assent may be necessary, so check with your IRB regarding their standards.

Advarra’s IRB requires an assent statement (separate signature block in the standard ICF) for subjects who are minors and old enough to understand the ICF as written (approximately 14-17 years old). An assent form is needed when younger subjects (approximately 7-13 years old) need the information presented in age-appropriate language. The IRB doesn’t typically require subjects 6 years old or younger to sign an assent statement or assent form.

Basic Elements of Informed Consent

The regulations are very specific regarding what to include in the ICF and what to exclude. The basic elements of informed consent are mandated by the Common Rule (i.e., Department of Health and Human Services [DHHS] Office of Human Research Protections [OHRP] regulations) and FDA regulations at 45 CFR 46.116 and 21 CFR 50.25 respectively.

To remain compliant with the International Council of Harmonization’s good clinical practice guidelines (ICH-GCP) for studies conducted outside the U.S., also consider the ICH basic elements. Note that many (though not all) ICH elements are well-aligned with U.S. requirements.

Remember that it is only necessary to include the regulatory elements applicable for a given study. For example, an FDA regulated study would not need to comply with the Common Rule unless there is also DHHS funding involved.

FDA and Common Rule Elements of Informed Consent

For research regulated by the Common Rule: ICF should begin with a concise and focused presentation of the key information most likely to assist a prospective subject in understanding the reasons why one might/might not want to participate in the research
Purpose of Research:
- A statement that the study involves research
- An explanation of the purposes of the research
- The expected duration of the individual’s participation
- A description of the procedures to be followed
- Identification of any experimental procedures
Risks and Discomforts: A description of any reasonably foreseeable risks or discomforts to the subject
- Cross-reference ICF language with risks in the protocol document and product information (i.e., Investigator’s Brochure)
Benefits: A description of any benefits to the subject (or to others) which may reasonably be expected from the research
Alternatives: Disclosure of appropriate alternative procedures or courses of treatment (if any) that might be advantageous to the subject
Confidentiality: A statement describing the extent (if any) to which confidentiality of records identifying the subject will be maintained
- If applicable, this section should also include a statement noting the possibility that the FDA may inspect the records
Compensation for Injury: Only required for research involving more than minimal risk: An explanation as to whether any compensation and/or any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained
Research Questions: An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject
Voluntary Participation: A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled
ClinicalTrial.gov information: Applicable for Phase 2 and later studies, must be verbatim as follows: A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.

Additional Elements of Informed Consent

Note: These elements are instance-specific, and their applicability is at the IRB’s discretion. To help streamline the review process, sponsors and sites should communicate with the IRB regarding the circumstances informing the addition or omission of these elements.

A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable
Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent
Any additional costs to the subject that may result from research participation
The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject
A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject
The approximate number of subjects involved in the study
For all NIH-funded research, and any other research for which a Certificate of Confidentiality (CoC) has been issued, a description of the CoC
If genetic testing results will be returned to the site and/or the subject, include information about the Genetic Information Nondiscrimination Act (GINA)
If infectious diseases will be tested for (i.e., tuberculosis [TB], HIV, hepatitis [B, C], COVID-19), a statement that results may be required by law to be reported to local health authorities
For research regulated by the Common Rule: For research with identifiable private information or identifiable biospecimens, a statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and the information or biospecimens could then be used for future research studies or distributed to another investigator for future research studies without additional informed consent
- OR a statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
For research regulated by the Common Rule: A statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will/will not share in this commercial profit
For research regulated by the Common Rule: A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions
For research regulated by the Common Rule: For research involving biospecimens, whether the research will (if known) or might include whole genome sequencing

For more information on informed consent, review: 21 CFR 50.20, 21 CFR 50.25, 45 CFR 46.116, 45 CFR 46.117, ICH Good Clinical Practice (GCP), FDA Information Sheet: Informed Consent, OHRP Informed Consent FAQs, Belmont Report, PlainLanguage.gov, NCCN Informed Consent Language Database

Note: This article was originally published April 14, 2022, and has been updated to include new and clarifying information.

The Food and Drug Administration (FDA) is the federal entity in the U.S. charged with (among other things) “ensur[ing] that safe and effective drugs are available to improve the health of the people in the United States.”

Before the FDA permits a pharmaceutical drug product to be lawfully marketed, sponsors are required to submit information about the product’s safety and efficacy so the FDA can determine:

“Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
Whether the drug’s proposed labeling (package insert) is appropriate, and what it should contain.
Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.”

The FDA requires the data for these assessments to generally come from animal studies and clinical investigations¹ of the investigational product(s)².

In addition to granting new drug approvals, the FDA is also the gatekeeper for whether a sponsor can conduct the clinical investigations necessary to gather the data required for drug approval. In other words, the FDA also regulates whether investigational products may be manufactured, shipped, and administered to human subjects who participate in clinical investigations.

This blog focuses specifically on the investigational new drug application (IND)³ and when investigational drugs may be manufactured, shipped, and administered in clinical investigations.

When Does an IND go into Effect?

An IND may only be used in a clinical investigation after the following steps are completed:

The sponsor of the investigation submits an IND to the FDA;
The IND goes into effect; and
The sponsor has received institutional review board (IRB) review and approval of a clinical investigation in accordance with FDA regulations at 21 CFR parts 50, 56, and 312. (21 CFR 312.40(a))

The FDA will send the sponsor an “IND Acknowledgement” letter or email after the sponsor submits an IND. This letter will include the date the FDA received the application. This is the date the sponsor should use to calculate when the IND goes into effect.

The IND goes into effect:

30 days after the FDA receives the application, unless the FDA notifies the sponsor the investigations described in the IND are subject to a clinical hold under 21 CFR 312.42; or
On earlier notification by FDA indicating the clinical investigations in the IND may begin (21 CFR 312.40(b))

The period between when the FDA receives the IND and when it goes into effect is often referred to as the “30-day hold.” It’s at the end of that period, unless one of the above criteria is met, when an IND automatically goes into effect.

When can a Sponsor Submit to the IRB?

Sponsors may submit research to be conducted under an IND to an IRB at any time before or after the IND is in effect. However, the research itself (including study-specific recruitment) may not begin until after the IND is in effect, even if the IRB has approved the research. (At Advarra, the IRB approval notice notes this requirement.)

When can a Sponsor Ship an Investigational New Drug?

Once an IND is in effect, a sponsor may ship the investigational product to the investigator(s) named in the IND application. The regulations at 21 CFR parts 50, 56, and 312 do not require IRB approval (in addition to the IND being in effect) before shipping the investigational product.

When can an Investigational New Drug be Administered?

A clinical investigation involving an investigational product may not begin until after both IRB review and approval have been obtained and the IND is in effect. This means in general, an IND can only be administered after both the IND is in effect and an IRB has reviewed and approved the research.

What About Amendments?

Sponsors are required under the IND regulations (21 CFR 312) to amend the IND as needed “to ensure the clinical investigations are conducted in accordance with protocols included in the application.” There are three types of amendments specified in these regulations:

New protocols
Change in protocol
New investigator

According to the regulations, sponsors must submit an IND Change in Protocol Amendments for “any change in a Phase I protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study.” (21 CFR 312.30(b)(1))

Examples of protocol changes requiring an IND amendment include, but are not limited to:

Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond the current protocol
Any significant increase in the number of subjects under study
Any significant change in the design of a protocol (such as the addition or dropping of a control group)
The addition of a new test or procedure intended to improve monitoring for, or reduce the risk of, a side effect or adverse event (AE)
The dropping of a test intended to monitor safety

Any of the categories of IND amendments may be implemented:

After FDA submission
After the IRB of record reviews and approves the IND amendment (i.e., new protocol, change in protocol, and/or new investigator)

Note a protocol change intended to eliminate an apparent immediate hazard to human subjects may be implemented immediately, provided the sponsor promptly:

Submits an IND Change in Protocol Amendment to the FDA after the change is implemented
Notifies the IRB of record of the change in accordance with the IRB’s policies and procedures

Can Recruitment Activities Begin During the 30-day IND Hold?

In general, no study-specific activities may begin before the IND is in effect and an IRB has reviewed and approved the research. This means study-specific activities such as advertising, eligibility screening, and seeking informed consent are prohibited during the 30-day IND hold.

The IND waiting period can be particularly challenging in Phase I research, where timelines are especially tight. When appropriate, consider speaking with your IRB to understand what recruitment-related activities might be permitted (or precluded) during the 30-day IND hold period.

It’s important to bear in mind: the 30-day IND hold is an FDA requirement. IRBs do not have the authority to change these legal requirements. It may be helpful to contact FDA for specific information regarding its IND review.

References:

¹Clinical Investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. (21 CFR 312.3(b))

²Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part. (21 CFR 312.3(b))

³IND means an investigational new drug application. For purposes of this part, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” (21 CFR 312.3(b))

A well-trained, effective, and efficient team is key to a successful clinical trial. Especially in the post-COVID world of changing work modalities, implementing a training program can seem more confusing than ever.

The forced exodus to all-virtual environments opened the door to more flexibility in developing and delivering training. With the changed landscape, training now has the potential for greater effectiveness and efficiency. Finding the best solutions starts with evaluating your training needs. Let’s review the breakdown of types, goals, principles, and strategies for ensuring you have a trained and effective team.

The Three Models of Site Training

With so much material to cover, it can be difficult to know where to start. Also, there are different ways to convey the same information. When thinking of the best training avenue for your audience, think of three common training models:

Live training: Always synchronous (scheduled/real-time interactions), delivered in person or virtually
eLearning: Delivered live, self-paced (asynchronous), or scheduled
Blended: Delivered in person and self-paced, live virtual and self-paced, or in an asynchronous cohort

Each model has its benefits and its drawbacks. Live training can be conducted in person or virtually. This type of training means immediate feedback, and gives the option for live coaching and community building. But live training is both tricky to scale up and more expensive, given the costs of travel, time, staff, and space. Additionally, the information is delivered outside of the work environment, meaning it’s decontextualized and possibly less sticky.

eLearning, which became ubiquitous during the pandemic, offers a unique set of benefits, including:

Improved knowledge retention
Consistency
Cost efficiency
Easy to scale and schedule

Keep in mind, however, eLearning programs require a big upfront effort and expense to develop, not to mention technologic proficiency.

A blended approach combining live and eLearning models is often the best of both worlds, facilitating knowledge retention, efficiency without losing contextualization, lower cost to productivity, scalable, easy to schedule, consistent, and can include live coaching. Again, scheduling and developing resources remain the key challenges for the blended model.

Training Principles, Motivations, Tools, and Success Metrics

Advarra looks at training through the lens of awareness and automation, in which the type of retention required drives the degree of automation used in the training. For example, if an employee needs to simply remember things, high automation – such as eLearning – may be perfectly sufficient. If an employee needs to understand and execute complicated steps, live training may be most appropriate.

Understanding the “why” behind training is crucial for adult learners. While the significance of communicating the training’s relevance is always important, it’s even more pressing in the context of eLearning. Here are four principles to follow when developing your training program:

Make sure your staff knows the “why” behind the material
Be clear on when and how they will use the skills they are learning
Use examples of past successes and highlight problems training solves
Offer ways the employee can continue training on their own via self-guided materials and other resources

Creating, Delivering, and Tracking Your Training

Fortunately, many of the tools necessary to create and deliver content are probably already in house. Content production tools include the Microsoft Office suite, Adobe suite, Articulate Suite, Google Suite, and smartphones. For content delivery, consider Zoom or other teleconference products, email platforms, messaging tools, QR codes, wikis, and SharePoint. To deploy, track, and measure results, consider Office Suite and/or Google Suite: O365 Power Automate, Google forms, wikis, the company’s intranet, and even a simple spreadsheet.

Metrics of Success

Finally, how do you assess a successful training? Has the information stuck for everyone? There are several metrics, from anecdotal to measurable success. Live trainings rely on staff feedback, user surveys, and the instructor’s impressions, as well as quizzes and/or projects, which is also useful for eLearning. A longer-term metric is simply on-the-job feedback from supervisors and job performance reviews. As your training program grows, keep track of the results and adjust your approach accordingly.

How Advarra Creates Scalable, Effective, and Efficient Training

No matter where you are in your company’s training program, Advarra Training can make it more effective with our three tiers of training, divided by effort through the lens of production and delivery.

Tier One: Easy-to-scale, high-production effort wherein the employee does the training virtually and asynchronously, with self-service access to existing content provided and delivered by Advarra.

Easily scaled, low effort
Client uses existing Advarra resources
Low effort by client involvement

Tier Two: Training involves low production effort and medium delivery effort, meaning we work together to adapt training materials to your needs. Materials can be streamlined but are not automated.

Scalable, but with more effort
Client pays for Advarra’s time
Train the Trainer and Trainer Bootcamp options

Tier Three: High production and delivery effort wherein Advarra creates training for your staff, finding novel solutions to novel problems and providing templated, non-automatic solutions where efficient.

Lowest scalability, has concentrated impact
Client pays for Advarra’s time, expertise, and access to unique resources
Includes contextualized training, paid product training, and certifications

As a partner, Advarra brings certain advantages, insights, and products, including learning management system (LMS) capabilities with a robust eLearning library, reducing the upfront burden of creating your own eLearning program. Learn more about our custom LMS portals, good clinical practices (GCPs) training, HIPAA learning program, and more.

A rare, or orphan, disease by definition affects a small percentage of the population — fewer than 200,000 people in the U.S. But the numbers add up, and taken together, rare diseases impact an estimated 30 million Americans. Orphan drugs have historically faced a number of barriers, such as limited research and development (R&D) investment due to an expected lack of profitability as well as challenges in clinical trial design and recruitment. Before 1983, only 38 orphan drugs had received U.S. Food and Drug Administration (FDA) approval. Since then, the FDA has significantly changed its approach to rare and orphan diseases.

The FDA Since 1983

The Orphan Drug Act of 1983 was instrumental in changing the number of orphan drugs approved in the U.S. The law established the Office of Orphan Products Development, providing financial incentives for pharmaceutical companies to develop orphan drugs and making it more viable to invest in orphan drug research and development. The impact was clear: Between 1983 and 2020, FDA approved 599 orphan drugs.

Since 1983, the FDA has continued to expand its attention to rare diseases and the drugs treating them. In 2016, the FDA granted 333 (57%) of the 582 orphan drug designation requests it received – nearly 10 times the number of designations the agency awarded in 1986.

The agency’s 2019 guidance, Rare Diseases: Common Issues in Drug Development, called attention to the need for natural history studies for rare diseases. The guidance provided the agency’s thinking on the design and implementation of such studies. It also broadened eligibility for orphan drug clinical trials conducted to demonstrate safety and effectiveness of orphan drugs. Today, nearly a third of all pipeline drugs are indicated for rare diseases, and the FDA continues to provide public support for awareness programs, such as 2022 Rare Disease Day.

FDA Expedited Programs

While the Office of Orphan Products Development is responsible for reviewing applications and assigning orphan designations, it is not involved in a drug’s approval. That is part of the responsibility of the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). These centers, in conjunction with the FDA and U.S. Department for Health and Human Services (DHHS), prepared guidance on expedited programs for sponsors of orphan drug trials.

Because most rare diseases are indeed “serious or life-threatening disorders with unmet medical needs,” orphan drugs may be able to take advantage of at least one of the FDA’s four expedited programs:

Fast-track designation: Helps get drugs treating serious and life-threatening conditions to market as quickly as possible
Breakthrough therapy designation: Gives priority review to therapies offering substantial advantages (based on early clinical trials) over existing options for patients with severe or life-threatening diseases
Priority review designation: Indicates the FDA’s goal of taking action on the application within six months
Accelerated approval: Allows drugs for serious conditions filling an unmet medical need to be approved based on “a surrogate endpoint”

Other FDA Orphan Disease Focus Areas

The FDA and the life sciences industry recognized the impact of the Orphan Drug Act and the advances in medicine over the past few decades. In order to support the continued need for rare disease drug development, the FDA took action to ensure they could continue to drive progress in this area. In 2017, the agency launched its Orphan Drug Modernization Plan, designed to help enable a “more efficient, scientifically advanced, predictable and modern approach to the approval of safe and effective treatments for rare diseases.”

In addition, the FDA funded the Rare Disease Cures Accelerator, which set out to facilitate cooperation and standardization to enhance the clinical trial process for rare diseases. This initiative includes a data analytics platform, RDCA-DAP. The platform aims to use standardized data to “inform rare disease characterization, clinical trial design and other critical questions in rare disease drug development.” By pulling together existing data and making that data available, RDCA-PAP seeks “to accelerate the regulatory approval of new therapies.”

A Lasting Impact

Through its various initiatives and programs, the FDA shows a demonstrated, increased effort in supporting the development of rare and orphan drugs. This is especially important as we consider roughly 90% of rare diseases have no approved treatment and orphan drug development takes 18% longer than the average time required for new drugs, according to the Tufts Center for the Study of Drug Development.

However, it remains important to plan and seek expert advice as early in the development process as possible. Partnering with experts with FDA and orphan drug experience is key to successfully navigating the regulatory environment for rare and orphan diseases.