When faced with a life-threatening condition, the decision to participate in a clinical trial is rarely taken lightly. For some Medicaid beneficiaries, the decision has been unnecessarily overwhelming, given financial barriers. The 

, which quietly went into effect in January, federally mandates Medicaid plans in all states cover routine costs for beneficiaries that participate in clinical trials. For context, 

 currently covers about one in four Americans, delivering healthcare benefits to individuals and families with low incomes. It’s also a key source of health coverage for many communities currently 

 in clinical research: nearly twice the proportion of Americans who identify as Black, Native American or Hispanic are enrolled in Medicaid.

Until this year, Medicaid was the only major US payer not required by federal mandate to cover routine costs associated with clinical trial participation. Medicare and most private insurance plans have been required to cover routine costs for years.

The Clinical Treatment Act enables more patients to potentially access investigational treatments through clinical trials. In clinical research, participant medical costs are typically split. Sponsors cover drugs or labs needed for research. Insurance covers routine costs a participant may incur during the trial, including doctor’s visits and emergency hospital stays, which can be costly.

The Clinical Treatment Act also supports a rising and overdue industry scientific and ethical imperative for more diverse trial participation; an imperative underscored repeatedly by the differences in disease causality, presentation, and progression in diverse patient populations, as well as divergence in drug safety and efficacy.

Today, many biopharmaceutical companies are leaning into areas they can largely control by exploring decentralized approaches, scrutinizing longstanding inclusion criteria that may inadvertently exclude certain demographics, and finding ways to compliantly cover non-medical participant expenses. They are helping to counter the often-earned mistrust of research within some communities, addressing physician bias and supporting programs designed to increase diversity among research teams. Depending on a patient’s income, geography, prior health system, and/or disease experience, among other factors, some combination of each will make all the difference for one person but not another.

Achieving diversity, equity, and inclusion goals in clinical research will require nothing less than a full-court press. Removing barriers for people who may be in economically precarious circumstances makes good sense, which is why part of a broader industry effort must continue to focus on medical costs and the role of insurance coverage. Even though the Clinical Treatment Act passed, there’s more to be done to ensure its intent is achieved.

Industry can play a big role here. Our government affairs colleagues can help ensure the mandate is fully implemented at the state level. Our clinical and commercial colleagues can inform healthcare providers, sites, and patient advocates of the coverage change and help ensure patient-facing educational materials are updated accordingly.

More so, we can do a better job communicating with all potential trial participants when it comes to cost—irrespective of insurance type. Trials demand patients take on many heavy-duty unknowns. They don’t know how well a study drug might work or what side effects may emerge. In this context, we can do more to remove ambiguity related to medical and non-medical costs. One area we can look to is the informed consent process, which requires the provision of clear information on what’s known to date about the investigational drug, the randomization approach, and other pertinent medical details.

In an era of rising health costs and opposition to surprise medical bills, and as we seek to engage more diverse communities—some of whom may be less familiar with and/or potentially more skeptical of research—reassurance about costs (both medical and nonmedical, such as travel expenses and time away from work) and clearer communications would go a long way in building and maintaining trust, and arm patients with as much information as possible, hopefully making the decision about whether to participate in a clinical trial easier.

, Head, Patient Voice Consortium, Syneos Health

Articles

A Closing Thought

In an era of rising healthcare expenses, reassurance about costs for patients in diverse communities is particularly important.

Addressing the Cost Barrier to Inclusive Clinical Trials

Decentralized clinical trials (DCTs) are here to stay, as demonstrated by international regulators’ recent commitments to the model. But while the approach offers a multitude of benefits, from expanding access to increasing cohort diversity, it can also serve to magnify existing challenges, such as managing medication adherence.

The benefits of DCTs have been well documented in recent years. The FDA’s 

Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry, Investigators, and Other Stakeholders,

 for example, says that technological advances have “revolutionized the ability to remotely obtain and analyze clinically relevant information”.

The guidance, published in January, said that using digital health technologies (DHT) for direct, frequent data collection in the home environment provides a broader picture of people’s daily lives and behaviors. In addition, technological solutions can capture information from those who might otherwise be unable to report their experiences, such as infants or people living with cognitive impairment, it said.

In Europe, the Accelerating Clinical Trials in the EU (ACT EU) initiative, part of the updated EU Clinical Trial Regulation, has also placed the spotlight on this new way of working.

 Launched by the European Commission, the Heads of Medicines Agencies, and the European Medicines Agency in January, the program lists enabling innovative trial methods and supporting the modernization of good clinical practice as being among its 10 “priority actions” for 2022.

Documents such as these are installing confidence in remote monitoring and giving the industry the framework it needs to embrace the potential of DCTs or at least a hybrid trial.

As we move into this new world, however, we must be cognizant of the pitfalls as well as the benefits of DCTs. Adherence to medication, long an issue in clinical trials, is one potential casualty.

Sponsors and CROs know that patients not taking their medication as prescribed can drain study power, even to the point of study failure, and lead to underestimations of drug efficacy. But they also need to be aware that DCTs can magnify the problem. The removal of at least some of the face-to-face contact between site and participant can impact on the person’s engagement with the trial protocol­­—a well-documented factor in poor medicine-taking behavior.

In addition, because DCTs facilitate a more diversified population, the potential for non-adherent patients may be increased. Currently, study teams can have a selection bias toward those patients they know to be disciplined in their medication-taking behavior. By facilitating broader inclusion, however, DCTs can serve to remove this site filter, and compound issues surrounding poor adherence to medication.

In recent years, a variety of DHTs that purport to solve the problem of adherence have emerged. Solutions that ask people to record every medication intake in an e-diary or submit videos of themselves taking their medicine, could be considered counterintuitive. They can place additional burden on the patient—the very thing remote data monitoring is attempting to avoid.

Other solutions, that combine the power of connected packaging and data analytics/visualizations, for instance, can provide a frictionless experience
for patients. Connected blister packs, smart bottles, or pre-filled syringes, for example, can collect the time and date of dose, and transmit it to a cloud-based platform. Algorithms conduct a sophisticated analysis of medication-taking behaviors and present the site staff with those visualizations. This enables them to spot patterns that might indicate “at-risk” participants, allowing for risk stratification and informing individualized interventions.

The approach can even be integrated into third-party applications, such as patient-facing mobile phone apps, which are designed to continually encourage adherence, and reinforce protocol engagement.

Digital adherence monitoring, then, gives site teams the ability to get to know participants, even when not meeting in person, thereby maintaining the human connection of face-to-face trials.

AARDEX has been working with sponsors and CROs to embed its evidence-based adherence tools into clinical trials for some time, and have concluded that there is no one-size-fits-all solution.

The right service or combination of services will depend on a variety of factors. It means that the best adherence management partner is one that can offer an ecosystem of solutions that can be matched to the needs of the trial and its cohort.

In February, for example, AARDEX started working with Trials@Home, a center for excellence for remote DCTs, on a Phase III study. It will include participants with type 2 diabetes across more than 60 sites in several countries. Of those, some will be site-based and hybrid, and others will be in the remote arm.

A monitoring tool will collect dosing data from Sanofi’s insulin pens, and send it via Bluetooth, to AARDEX’s MEMS® Adherence Software for analysis.

The study, due to end in August 2024, aims to provide an optimal understanding of patient behaviors. The insights could help improve medication adherence in a patient cohort where non-adherence has a direct causal association to hospitalization and mortality.

In Australia, the University of Sydney and the University of New South Wales took a different approach when they used AARDEX’s digital solutions to verify adherence during a clinical research project.

The study, to determine whether the self-monitoring of serum uric acid concentrations improved adherence to the urate-lowering drug allopurinol among people with gout, enrolled participants for one year follow up.

They chose AARDEX’s MEMS® Cap, a customizable smart package, and the MEMS® Mobile for Research app, which participants downloaded to their own phones in a bring your own device (BYOD) model that kept costs to a minimum.

Participants used the app to access their time-stamped dosing events from the smart package and transmit the data to the MEMS AS® software. This allowed the team to collect and review dosing information in real time so as to spot erratic dosing patterns and provide additional support when needed.

Patients were also able to send comments to the study team via the app, which staff said had helped to increase engagement

DCTs are fast becoming the new normal, as they offer huge benefits for more streamlined, patient-centered trials. But if we are to fully embrace the advantages, we must be aware of the pitfalls as well. Remote data monitoring can magnify the issue of poor medication adherence as it risks eroding the relationships that can keep people engaged in the protocol.

However, when tailored to the needs of the trial and the cohort, digital adherence monitoring wraps its arms around participants. And in doing so it provides a frictionless solution that informs targeted interventions and re-establishes the all-important connection between site and patient.

Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. 2022. Available at: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations

Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative. 2022. Available at: 

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/accelerating-clinical-trials-eu-act-eu-delivering-eu-clinical-trials-transformation-initiative_en.pdf

Vrijens B, Urquhart J. Methods for measuring, enhancing, and accounting for medication adherence in clinical trials. 

. 2014 Jun;95(6):617-26. doi: 10.1038/clpt.2014.59. Epub 2014 Mar 12. PMID: 24739446.

Balkrishnan R, Kulkarni AS, Cayce K, Feldman SR. Predictors of healthcare outcomes and costs related to medication use in patients with acne in the United States. 

Muddasani S, Heron CE, Fleischer AB Jr, Feldman SR. Time Intervals Until the First Return Office Visit After New Medications.

. 2020 Dec 1;19(12):1226-1230. doi: 10.36849/JDD.2020.5542. PMID: 33346517.

Example of AIcure: Larsen KG, Areberg J, Åström DO. Are self-reported and self-monitored adherence good proxies for reaching relevant plasma concentrations?: Experiences from a study of anti-depressants in healthy volunteers. 

. 2021 Aug;18(4):505-510. doi: 10.1177/17407745211012683. Epub 2021 May 2. PMID: 33938259.

Thomas, B. E., Kumar, J. V., Chiranjeevi, M., Shah, D., Khandewale, A., Thiruvengadam, K., ... & Subbaraman, R. (2020). Evaluation of the accuracy of 99DOTS, a novel cellphone-based strategy for monitoring adherence to tuberculosis medications: comparison of DigitalAdherence data with urine isoniazid testing. 

Feature Articles

Assessing the benefits of digital adherence monitoring for sites and patients.

DCT Risk/Benefit Profile: A Focus on Adherence

We have heard it from local clinical trial regulatory departments, hospitals, and country-level regulatory experts: “participant records cannot be shared by the investigator outside of the site.” The well-meaning declarant adding, “it violates GDPR.” That phrase has likely burned many protocols’ hopes and dreams of decentralized assessments in the European Union (EU). But is that statement true? This common interpretation of the good clinical practice (GCP) confidentiality principle may deter investigators from sharing study participants’ directly identifiable and health information with third-party home health providers in decentralized clinical trials (DCTs). However, a thorough reading of GCP demonstrates how an investigator may share identifiable participant information with third-party vendors in compliance with applicable GCP confidentiality requirements and the protections offered data subjects in the EU by the General Data Protection Regulation (GDPR).

It is important to be mindful that prior to determining that it is appropriate to include decentralized aspects in a clinical trial, the sponsor has conducted a risk-benefit analysis of the specific assessments that are proposed to be conducted remotely in the study.

Identify and assess the risks to participant safety and the collection of reliable data that could be posed by conducting an assessment outside of the site.

Identify potential benefits of the remote assessment to the study participant and data collection.

Include consideration of how appropriate oversight of the remote assessment and third-party vendor by the investigator is accomplished.

After these assessments are made determining that, for example, remote assessments by healthcare providers—so-called “home health visits”—are appropriate, the DCT protocol may include home health visits on its schedule of assessments. In a home health visit, a healthcare provider may meet with the study participant at the participant’s home or other off-site location to support the conduct of the clinical trial, including remote assessments (e.g., blood draw by a phlebotomist or nurse-administered medication).

GCP protocol-related activities are to be conducted by the investigator or through delegation and under supervision of the investigator, by a person determined by the investigator to be qualified by skill, education, and training to perform the task. Due to site staffing constraints or logistics, often a third-party vendor is retained to conduct these assessments.

To be able to perform the protocol-related tasks, the vendors must access the directly identifiable information of the participant. This may include the participant’s name, phone number, and email address to communicate with the participant to make appointments, home address for travel and planning, and year of birth to validate identification prior to the assessments.

This access by third-party healthcare providers to participants’ identifiable information is sometimes flagged by ethics committees, investigators, or country-level regulatory experts as a potential participant confidentiality concern under GCP or GDPR. Often, the concern is, in fact, a confusion of an investigator’s regulatory obligation to protect the confidentiality of participant identity and medical records with a misunderstanding that there is a complete prohibition to sharing that information with a person other than the investigator’s staff.

GCP requires that all reasonable precautions should be taken to protect the confidentiality of participants within the applicable regulatory constraints. This means that access to information that identifies the participant should be restricted to authorized parties, as needed, to conduct the trial or to audit the study for the protection of the participants and data quality.

In the case of the home health professional example earlier, the investigator verifies the qualifications of the third-party home health professional. In addition, the investigator reviews study plans for information regarding how the participant’s identifiable information will be handled by the home health professional to ensure that the information will be adequately kept confidential by the third-party vendor. This information may include results of due diligence reviews conducted by the sponsor into the third-party processes or systems that will handle participants’ directly identifiable information.

Once the investigator is satisfied that the third-party home health professional is qualified by training and skills and that appropriate processes and systems will be utilized to conduct the protocol-required activities, the home health professional will be formally delegated certain tasks in support of the study and added to the site delegation log.

Confidentiality is appropriately safeguarded when the investigator has reviewed in the study plan how the third-party nurse, for example, will conduct the visit and is assured that the nurse’s processes will also keep the participant information confidential. This additional review into the “qualification” of third-party vendors as required by GCP would not be required of the investigator but for the sponsor’s requirement of a remote visit in the protocol.

Investigators may seek reasonable reimbursement for their time and resources in making this important determination into qualification of the third-party vendor. Investigators may also seek assurances as to the results of any due diligence of the sponsor into the systems and processing of the third-party vendor and, therefore, may not need to complete their own assessments of complicated technical systems, which may be beyond the expertise of most investigators.

In this example, there is not a total ban on sharing the participants’ identifiable information, but instead a) review of the qualifications of the nurse; b) review of study plans to ensure the nurse will maintain confidentiality of the participant’s information in their processes and/or assurances by the sponsor as to results of the due diligence it performed on the vendor; and c) traceable documentation of the tasks delegated to the nurse, to substantiate the need for the investigator to share participant data (delegation log). In this instance, the investigator has taken reasonable precautions to protect the confidentiality of the participants and acted in accordance with GCP requirements.

GCP was initially adopted in the International Conference on Harmonization (ICH) revision 1 (R1) in the 1996 guideline, when most of the world was first experiencing e-mail. The 2016 revision 2 addendum (R2) improved content on the use of electronic systems but did not alter the language around confidentiality.

In 2022, ICH is preparing for the Revision 3 (R3) of the guideline. There is ample indication that, with this revision, the guideline will be brought into the decentralized era of clinical trials. About the principles of GCP, ICH writes: “The principles are intended to support improved and more efficient approaches to trial design and conduct.”

In its working paper for R3, the ICH working party addresses the perceived problem with trial design and conduct by including guidance for emerging technologies, innovations in trial designs, diversity of data sources, service providers, and other emerging complexities of today’s clinical trial designs.

In review of draft R3, for example, the principle around confidentiality has been altered, referring more directly to the privacy and data protection regulations. Draft R3 now reads: “The confidentiality of information that could identify participants should be protected in accordance with applicable privacy and data protection regulations.” The move from “confidentiality of records” in the current R2 to “confidentiality of information” that could identify participants in R3 is not insignificant. The revised language recognizes that participants’ identifiable information is not only hospital records but may be in other forms, possibly electronic systems—thus acknowledging that the confidentiality of information may be maintained outside of hospital records. The revision maintains the term “protected,” includes language around quality management, and takes a risk-based approach to the protection of trial participants. The revision requires identifying the critical processes for participant confidentiality, identifying, and evaluating potential risks and deciding on risk control measures and quality tolerance limits, prior to the beginning of the study. Thus, R3 seems to contemplate a scenario like the third-party nurse example earlier, where after adequate risk assessments by the sponsor and due diligence by the investigator, participant identifying information is accessed by third parties and yet confidentiality is protected in accordance with GCP.

Data protection laws (DPLs), including the GDPR, are a second, independent set of regulatory requirements applicable to clinical trials. While DPLs are fully distinct from GCP, the requirements of DPLs and GCP contain some similar provisions with respect to protecting personal data and maintaining patient confidentiality. However, it is critical that the specific requirements of both GCP and DPLs are independently considered and addressed.

For DPLs, that means providing proper notice and receiving consent to processing study participants’ personal data, utilizing adequate technical and organizational security measures, preventing access by or transfers to unauthorized parties, disclosing processing of the data by third parties, and limiting use of the data to the purpose for which it was collected.

Each of the DPL requirements identified in this article are consistent with the GCP principle for maintaining participant confidentiality. In some cases, such as information security, the same controls can satisfy the requirements of both GCP and DPLs. But care must be taken to avoid assuming that compliance with either GCP or a DPL automatically results in compliance with the other.

This brings us back to the quotation in first sentence of this article, “participant records cannot be shared by the investigator outside of the site…it violates GDPR.” While it’s a mistake to assume that satisfying one set of requirements means automatic compliance with the other, it’s also erroneous to assume that the GDPR is being violated without checking the statute. A careful review will show that if certain conditions are satisfied, the GDPR is not a barrier to sharing participant records outside of the site.

With the appropriate reviews of the third-party provider’s training and qualifications, confirmation that the third-party providers will protect participants’ confidential identifiable information and completion of delegation logs, the investigator may, in fact, share participant identifiable data with third-party providers in accordance with GCP and GDPR’s confidentiality requirements. Investigators should document their efforts to “qualify” these third-party vendors and the results of sponsor’s due diligence reviews of the vendor, in accordance with GCP, and may seek reasonable reimbursement for these efforts from sponsors of clinical trials. Future iterations of GCP are likely to make this approach to confidentiality of participant information clearer, underscoring the pre-trial risk assessments of sponsors and investigators.

The resolution of these issues and adoption of these practices will help relieve sponsor and investigator concerns of how remote assessments in DCT by third-party home health providers will be viewed in audits and inspections. 

, Senior Director, DCT Regulatory and Data Privacy, IQVIA Virtual Trials, IQVIA

Alleviating sponsor and investigator concerns around sharing of 
remote-assessment data in accordance with GCP and GDPR standards.

Confidentiality in DCT: How to Utilize Third-Party Home Health Providers

Digital therapeutics (DTx), the use of software-based interventions to prevent and treat disease, is one of the biggest areas of growth in life sciences. CB Insights reported that 2021 funding in the digital health industry grew 79% over 2020,

 and the global DTx market is projected to hit $13.1 billion by 2026, up from $3.4 billion in 2021.

 Many say digital therapeutics will rewrite the future of healthcare.

While it sounds aspirational, the DTx industry isn’t just “pie in the sky.” Studies show improved outcomes from digital therapeutics, either alone or in conjunction with conventional therapeutics, in a broad range of indications, including cancer, ADHD, asthma, schizophrenia, and insomnia. Some examples of products include video games to treat mental- and behavioral-health issues; a digital therapeutic platform that incorporates neurological music therapy, sensors, and AI to help patients who have suffered a stroke or other neurological disorder to rebuild motor skills; and a smartphone app that can conduct electrocardiograms anytime, anywhere.

Successful DTx companies have capabilities in areas that many biopharma companies traditionally do not: big data and advanced analytics, hardware engineering, and human-centered product design. Such capabilities will probably prove essential for pharmaceutical companies as healthcare evolves toward a digital future, but—for now—a growing number of pharmaceutical companies are seeking to explore these capabilities by partnering with DTx companies and developing combination products.

“It’s a good match—agility from DTx startups and scale from big companies,” said Bozidar Jovicevic, former head of digital therapeutics at Sanofi. In 2019, Sanofi partnered with Happify Health to produce a DTx app to improve mental health in patients with multiple sclerosis. The product is in a proof-of-concept decentralized trial with several thousand MS patients.

 The first FDA-approved digital therapeutics was Pear Therapeutics’ reSET app to treat substance abuse, launched in partnership with Novartis’ Sandoz unit in 2018.

While the industry is optimistic about the promise of DTx, manufacturers are still navigating unchartered territories around the best practices for clinical research. Likewise, pharmaceutical companies seeking to tighten partnerships with DTx startups to innovate combination products, find themselves in clinical trial limbo.

Often, DTx manufacturers and drug manufacturers who are exploring DTx pairings seek efficacy-validating evidence through clinical trials to earn the confidence of consumers and the attention of payers so that they can get their products reimbursed. FDA or European Medicines Agency (EMA) approval is not always the end goal.

AstraZeneca, for instance, has designed a rigorous and low-patient-burden digital therapeutic to monitor metastatic breast cancer patients. The prescription 

, which is currently being tested in clinical trials in 23 countries, was developed using insight from a review of medical literature, pulmonary and breast cancer experts, technology review, and real-world evidence gathered through conducting a deep cohort analysis of approximately 500 patients in US health systems. The therapeutic’s aim is to monitor patients’ symptoms and vital signs and, based on algorithms and expert rules, alert a physician as to how well the patient is doing on the treatment to maximize both safety and outcomes.

“Regulation will differentiate between a fitness app a consumer can simply download, with no regulation required, versus something that is scientifically proven to have a direct impact on someone’s health condition or outcome, which a doctor may prescribe,” said Cristina Duran, chief digital health officer for AstraZeneca, in a statement. “In a few years, I think we will see that shift to it being commonplace for your doctor to prescribe a digital therapeutic, a medication, or both.”

On top of today’s regulatory limbo, manufacturers face several additional clinical challenges, including patient recruitment and retention, quality of data, and high costs. At the same time, clinical trial models are rapidly evolving, adding further complexity to companies working to develop innovative digital therapeutics in a post-pandemic environment. Decentralized clinical trials (DCTs) are becoming more common as the preferred model for research in biopharma and offer similar—if not even greater—value to companies conducting studies on digital therapeutics.

Fundamentally, a DTx is software rather than a pill or injectable, so there is no distribution or administering of medicines. There are no physical logistics—no shipping, storing, chain of control, cold storage, or biohazards; plus endpoints can be captured within the DTx application itself, making DCTs ideally suited for DTx studies whether seeking regulatory approval or consumer and payer confidence.

The following are three ways DCTs enable DTx development.

DCTs boost patient recruitment, retention, and engagement

Patient retention and engagement have long been challenges in clinical research, but DCTs have had a uniquely positive impact on digital therapeutics studies. DCTs make participating in research easier and studies more accessible to participants who live far away from study centers. Without the need to perform all assessments at a clinical trial site, sponsors can successfully recruit patients from greatly expanded geographic areas. Opening studies up to more participants, optimizes the patient pool, and reduces the need to over-enroll based on anticipated attrition or drop-out rates to improve cost efficiency.

One emerging DTx company that uses a cognitive behavioral therapy to create mobile apps aimed at managing and preventing chronic diseases recently initiated a DCT for its latest digital therapeutic. The product is designed to measure and unveil early detection, management, and de-escalation opportunities for individuals who are at risk for, or are managing, cardiovascular disease. The decentralized model was a natural fit for the midsize company.

The study’s principal investigator said the company chose a DCT versus a traditional brick-and-mortar trial model to improve and diversify patient recruitment as well as to remove population bias. “Patients are starting to demand more convenient methods of participating in research,” she explained. “DCTs remove so many burdens that stand in the way of recruiting patients for trials.”

Mike Aratow, MD, FACEP, co-founder and chief medical officer of Ellipsis Health, a DTx company that developed the first voice vital sign to quantify and manage depression and anxiety at scale, also noted the significance of DCTs on patient recruitment. “A decentralized model not only aids patient recruitment because it removes many of the burdens associated with traditional trials, but it also makes it easier to reach underrepresented groups and those from a wider geographic landscape, providing real-world evidence and ecological validity. In traditional research, a significant amount of the medical data can’t be reproduced due to issues around patient retention and patient participation.”

Feel Therapeutics develops digital biomarkers and therapeutics for mental health using a proprietary wrist-worn wearable device.It monitors various physiological signals continuously to extract metrics and insights on patients’ psychological and physical health. Feel CEO George Eleftheriou agrees that DCTs help optimize patient recruitment and improve engagement and retention.

“Wearable and digital technologies remotely measure endpoints while engaging participants in an unprecedented way, which naturally aligns with digital therapeutics that are intended to integrate into patients’ everyday lives,” he said. “It is indicative that participants in our digital programs use our app for over 55 minutes per week.”

Decentralization improves cost efficiency

predicted the global DTx market would hit $9 billion by 2025, but a year later sharply upped that forecast to $56 billion.

This boon is largely driven by the surging need for therapeutic treatments for chronic and behavioral conditions—areas where digital therapeutics thrive. Despite this market growth, the DTx industry is still in its infancy with most companies considered start-ups with modest resources. Cost efficiency is central to their success—and another reason why a decentralized clinical trial model complements the DTx business strategy.

DCTs save costs, in part, by saving time. For instance, the single biggest time drain in drug clinical trials is patient recruitment, which can take up to 30% to 40% of the duration of the entire trial process and contribute to a study’s high price tag. Similarly, recruiting a diverse patient population and keeping them engaged for DTx studies is draining. By expanding the geographic area for recruitment, DCTs speed recruitment across a more representative patient population. By removing many of the burdens incurred by traditional trials, too, DCTs decrease drop-out rates in DTx studies.

In addition to the financial windfall that comes with saving time, DCTs require less staffing and eliminate the need for sites and infrastructure. In fact, for many growing DTx companies, lengthy brick-and-mortar trials are overkill as they don’t have the same scope or needs as a randomized Phase II FDA study for a new pill. The DCT model enables researchers to customize digital therapeutics trials based on exact needs, scaled according to their unique patient population and commercialization strategy.

For example, often the technology that DTx companies need to run a trial is materially different from the technology needed for a trial studying traditional medicines. Further, much of the software needed for a DTx trial is already baked into the DTx app being studied, so many of the robust components required for traditional clinical trials involving prescription drugs are not needed. DTx companies can save substantially—reducing the costs by a factor of 20 or more—by cherry-picking just the technology needed to run the DCT rather than paying for the full functionality of a comprehensive application. Curavit saved one DTx company $375,000 just by using a scaled back ePRO built into the digital therapeutic app rather than investing in an elaborate, name-brand system to do the same.

This benefits the patient, too. Patients who use one app to complete all trial forms find participation much easier than using different devices or going into a site for repeat visits. Again, a better patient experience decreases study drop-out for even greater savings and improved trial data.

Decentralized trials enable DTx companies to collect real-world data direct from patients where they are most comfortable, which has quantifiable impact on data quality.

Erik Won, MD, president and chief medical officer of Wave Neuroscience, a DTx company that specializes in treating brain disorders and optimizing brain performance, explained, “DCTs increase the quality of data by minimizing the Hawthorne Effect—a reactivity in which individuals modify an aspect of their behavior in response to their awareness of being observed, also known as ‘white coat syndrome’—because patients are in their home environment.”

Won continued, “With a decentralized trial, we get the best of both worlds. We can use other mechanisms to ensure that patients are following protocols while ensuring compliance. For instance, we record EEGs using wearables and ask patients to complete simple online surveys.”

Ellipses Health’s Aratow added, “By going to patients rather than having them come to us, the data collected is far more accurate and reflects real- world evidence.” Ellipses Health captures authentic voice using a mobile app so patients can stay comfortably in their homes.

DCTs also enable DTx researchers to capture data and endpoints directly within the therapeutic itself for seamless data capture and less potential for “lost” information. Patients can complete a survey on the same device (i.e., iPhone) as the app, improving engagement and reducing burdens. While the same benefits can be achieved for traditional drug product trials, these require an additional device or piece of software such as an ePRO, whereas a DTx trial participant only must learn and use a single app.

“DCTs enable us to collect passive, continuous, and objective data from users 24/7/365 and move from episodic patient-reported outcomes to continuous data collection,” added Feel’s Eleftheriou. “This rich data provides real-world evidence and allows us to explore novel biomarkers or digital endpoints in neuroscience and other chronic conditions with a high prevalence of mental health comorbidities, such as MS, certain cancers, and cardiac problems.”

DTx companies operate in a nebulous regulatory environment, even as the FDA works to clarify requirements. For example, the agency has demonstrated its commitment to supporting digital health technologies recently through the publication of multiple relevant guidance documents as well as the founding of the Digital Health Center of Excellence (DHCoE) in fall of 2020. The DHCoE provides regulatory advice and support to the FDA’s regulatory review of digital health technology, claiming that it is “setting the stage for advancing and realizing the potential of digital health.” In April 2021, too, the FDA loosened regulations surrounding approval of digital mental health tools to hasten their time to market.5

Yet, the regulatory landscape is complex, evolving quickly, and differently in each country. Regulatory approval is not always required to go to market, disincentivizing studies. Many DTx manufacturers are left to make decisions on their own on whether they choose to seek regulatory approval, depending on their commercialization strategy. It’s also challenging to design comprehensive clinical studies for novel treatment approaches, and expensive to run them. Most companies are taking a bifurcated approach—seeking FDA approval for one variation of their product and not for another, while leaning into the DCT model to gather convincing evidence and stand out from the competition, plus earn trust from patients.

Wave Neurosciences follows FDA guidelines for conventional trials, while also finding ways to adapt these in non-FDA studies to maintain regulatory compliance. The company references these as “bridge” studies—in other words, a clinical trial that is smaller, faster, less expensive, and designed to gather enough validated data to determine if taking the next step to an FDA-approval study makes sense. In these cases, especially, a DCT model makes it much easier and faster to conduct a bridge trial for DTx companies looking to determine what the next best steps should be for their product and commercialization strategy.

“All DTx manufacturers, whether a pharmaceutical company dabbling in this area or a pure DTx company, want payers and patients to be confident in their therapeutics’ efficacy, safety, and economics,” said Wave’s Won. “We leverage the flexibility of a decentralized trial to capture the data we need to get our products on formulary, even if we don’t always apply for regulatory approval.”

The marriage of digital therapeutics and digital trials

There’s still a lot to be learned in the digital therapeutics market, but they are here to stay with growing reliance, trust, and adoption of digital health products. COVID-19 pushed researchers to lean into the decentralized model for research, and the pandemic has simultaneously fueled a growing need for DTx products—an ideal marriage of process and product. While it’s true that many of the same benefits of DCTs that apply to traditional drug trials governed by the CDER also apply to DTx apps governed by CDRH, DCTs may offer even greater value to any company manufacturing DTx either in combination with other medicines or alone.

“Digital Health Funding Jumps to New High,” by Nick Paul Taylor; 

“Global digital therapeutics market projected to reach USD $13.1 billion by 2026,” ReportLinker (July 2021). 

“The Growing Power of Digital Healthcare,” by Bill Taranto; 

“Sanofi Breaks into Digital Therapeutics with Mental Health App,” by Beth Snyder Bulik; 

“DTx Trends and Companies to Watch in the Growing Digital Health Industry,” 

How DCTs can impact pharmaceutical companies exploring DTx 
combination products and standalone DTx studies.

Digital Therapeutics and Decentralized Trials: A Match Made in Clinical

This article is part of a series on the results of the Center for Information and Study on Clinical Research Participation (CISCRP)’s 2021 Perceptions & Insights Study. Nearly 12,000 people worldwide responded to the online survey—including the public, patients, and study volunteers—and provided insights into opportunities to improve global clinical research education, outreach, and engagement.

There have been widely publicized articles detailing how the COVID-19 pandemic has brought increased attention to clinical trials among the public and magnified the importance of including diverse populations in clinical research. But few reports have emerged on the impact of various diversity and inclusion campaigns on awareness and enrollment measures among underrepresented communities, with many of these campaigns launching during the height of the pandemic and focused on COVID clinical trials.

In promising news, our latest study identified pronounced increases in the general levels of awareness of clinical research among members of these underrepresented communities compared to their white and Non-Hispanic counterparts, suggesting that some of these targeted campaigns may have had an effect on these measures. As such, one must consider what types of efforts are most effective at engaging individuals from diverse backgrounds and, more importantly, should be implemented in the long-term. This article highlights findings from our latest study and explores the answers to these important questions and implications for the future.

When initially surveyed between April and July of 2021, more respondents reported that they heard of clinical research studies looking for volunteers in the last six months compared to previous studies. Among all survey respondents, a significant increase in awareness of clinical research studies seeking volunteers was reported (63%) compared to 2019 (54%). This increase may be attributed to the COVID pandemic, as most respondents reported their awareness either somewhat or greatly increased (74%), while only 25% reported “no change” in awareness.

Awareness of clinical research studies looking for volunteers was significantly higher among both Black (69%) and Hispanic (71%) respondents (see Figure 1 below), as compared to those identifying as white (62%) or Non-Hispanic (61%). Such findings may indicate that efforts to engage and enroll a more diverse population into clinical trials were effective in reaching members of those communities. When asked how they became aware of clinical research studies looking for volunteers, top-cited sources for both Hispanic and Black respondents included: social media sites (38%, 40%); traditional advertisements (e.g., on TV, newspaper, radio; 37%, 37%); and online advertisements (31%, 35%).

Individuals from diverse racial and ethnic backgrounds were also more likely to report being asked to participate in a clinical research study, which may be indicative of outreach efforts and their success.

Nearly two-thirds of Hispanic respondents (65%) reported being asked to participate, compared to only half (52%) of Non-Hispanic respondents. Similarly, Black (65%) respondents were significantly more likely to have been asked than their white counterparts (52%).

Targeted communications were the primary source of how individuals reported being asked to participate. In particular, “an email from a research study center or patient recruitment company” was the top-reported channel by which Black (31%) and Hispanic (22%) individuals were asked to participate. Subsequently, “through social media (e.g., Facebook, Twitter, Instagram)’ was the second-highest identified method of engagement among individuals from diverse racial and ethnic backgrounds, including Hispanic (20%) and Black (19%) respondents.

Underlying awareness in clinical research is elevated at this time, helping to drive greater use and demand for highly targeted and personalized approaches to attract a more diverse community of study volunteers.

Proactive outreach methods, including email campaigns and social media channels, appear to be particularly effective at reaching these underrepresented communities. 

, PhD, Associate Director, Medical Writing, CISCRP, 

, Senior Director, Research Services, CISCRP, and 

News

Latest CISCRP study provides insight on proactive outreach.

Awareness of Clinical Research Increases Among Underrepresented Groups

Rik de Greef, senior vice president of global quantitative science services at Certara, a biosimulation software and technology company, recently answered questions from 

 on the organization’s training initiatives in Africa, viewed by Certara as an untapped pool for talent in pharmacometrics.

Though a well-established part of drug development, demand for biosimulation—the use of computer-aided models to simulate complex biological systems—is growing, necessitating the need for more experts, the company says. 

: What inspired the Applied Pharmacometrics Training Fellowship in Africa and Certara’s investment in the program?

The fellowship program has been inspired by a number of factors that have nicely come together. Firstly, Pharmacometrics Africa has been providing training opportunities to many Africa-based scientists over the past years, which has brought them in touch with the methods and concepts of pharmacometrics. Still, a need was felt to train these scientists more in the applications of pharmacometrics to support decision-making in drug development. Certara shared this interest, as it wanted to broaden the global pharmacometrics talent base to be able to accommodate the demand of pharmaceutical clients for this bespoke skill set. Lastly, the academic and pharmaceutical partners are happy to contribute to the training of scientists from low- and middle-income countries but lack the infrastructure to do so. Our program brings these elements together and aims to concretely deliver a team of Africa-based pharmacometricians.

: The announcement said that the first cohort would start in January 2022. How is that inaugural class progressing?

Indeed, the inaugural class started with a virtual program in January. At this moment, the class is halfway through that part of the program. The class meets several days per week for classroom training and discussions. The students are very engaged, which makes for a great dynamic between them and the faculty of experienced pharmacometricians.

: When are you taking applications for the next cohort?

We are planning to run the program yearly. So, we probably will be taking applications for the 2023 cohort in the last quarter of this year.

: Are there specific challenges to teaching the doctorate-level scientists virtually in Africa?

There are no specific challenges to the teaching, it is the same as any type of virtual training environment. As faculty, you want to make sure that you maintain the engagement of the students during the training classes and in the course assignments.

: The press release stated: “Successful fellows of this program will be considered as candidates to form the first Certara consulting team located in Africa.” What is your timeline for that?

We are on track to have the first Africa-based consulting team for Certara start toward the end of this year, 2022.

Read more about Certara’s plans in Africa in ACT March’s Closing Thought 

Rik de Greef, senior vice president of global quantitative science services at Certara discusses the organization's training initiatives in Africa. 

Program Aims to Tap Africa's Potential in Pharmacometrics

The decentralized clinical trial (DCT) movement has become the “it” word in the post-pandemic clinical trials world. In cases of enormous hype, where a term is used over and over, as well as used as an umbrella term to mean multiple things, it becomes less descriptive and, therefore, more confusing.

Now when decentralized clinical trial articles are submitted to our editors, they must begin with what the core article topic is…not decentralized trials, not a historical restating of the facts of how DCTs came to be…not a reairing of all the possible benefits DCTs could bring to the industry. No. What we need now are specifics. Directions. Best practices. Or even things that were tried and didn’t work well.

But what I will concede is that DCTs have brought a whole new cast of characters into the clinical trials mix. And old characters proving that adaptability makes competitive sense.

For a complete and thorough explanation of an example of the new cast of characters, please read our 

. Here we learn about the challenges of the digital therapeutics industry and how it has grabbed on to DCTs as a way to more easily, and hopefully less expensively, acquire the needed quality data to ensure, at the minimum, outcomes evidence, and, at the maximum, FDA approval. With digital therapeutics, decentralized clinical trials providers such as Curavit Clinical Research or Curebase see a natural kinship or extension of those products with their digitally optimized clinical trials processes. While not the same pathway as a CDER- or CBER-based clinical trial, the needs for patient safety and scientific rigor are no less for a digital therapeutic that is going to make a claim to prevent, manage, or treat a medical disease or disorder.

As for traditional CRO providers, including Rho and PPD, their contributions to advancing DCTs can be found online. Rho has developed its RBQM strategies around a whole new host of 

 that can arise in a DCTs. And PPD’s example of using a mobile RV, a literal DCT on wheels, to ensure the continued participation of a rare disease participant. And again in an 

, designing the protocol so that both investigator and participant could customize their trial to fit the patient’s needs.

We look forward to sharing the use cases, examples, best practices, and more for the hybridization of clinical trials. “Decentralized” may have worn out its welcome, but the term sticks.

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

From the Editor

DCTs’ Broader and Multifaceted Implications

Issue PDF

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Applied Clinical Trials April 2022 Issue (PDF)

Anyone interested in exploring the use of complex clinical trials or who has skin in the game of running trials for combined advanced therapy medicinal products (ATMPs) may find something coming their way in new European opportunities for funding and support over the coming months. A leaked draft of the health plans under consideration for the next stage of the European Union's Horizon research program gives some insight into what is likely to result later in the year in a formal invitation for proposals.

The EU wants—according to the leaked text—to create a "diverse and comprehensive" landscape of multi-country adaptive platform trials that is "able to study multiple interventions in a disease or condition in a perpetual manner, thus allowing modification to the trial after its initiation without undermining its validity and integrity." That itself is no secret: it has been a part of European doctrine for close on a decade. But it has been given new impetus by attempts to tackle the coronavirus pandemic, because of the potential to assess medical countermeasures for infectious diseases. "The conduct of perpetual adaptive platform trials, with the in-built agility to pivot when an epidemic strikes, is key to be prepared for infectious disease epidemics or pandemics," says the document.

So the EU is now contemplating putting new money behind innovative designs of clinical studies suited for pandemic preparedness, in order to place additional expertise within the clinical research community when the need arises. It is also looking favorably on efforts to create trial sites across multiple countries with the capacity to deliver robust clinical evidence in a diverse European population. They don't even have to be created primarily for studies of pandemics. Adaptive clinical platform trials that are implemented routinely outside of an epidemic or pandemic context could qualify for support if they are designed to be ready also for rapid assessment of novel diagnostics, therapeutics, or vaccines in the face of an epidemic or pandemic.

Successful proposals are likely to be able to demonstrate the ability to sustain multi-country adaptive platform trials with adequate trial implementation capacity, laboratory analysis capacity, and a harmonized approach to the collection, storage, sharing, and analysis of data. They will take into account sex, gender, age, ethnicity, and socioeconomic factors, and hurdles related to ethical, administrative, regulatory, and logistical aspects "should be anticipated and addressed." A focus on the European regulatory environment is another ingredient specified in the plan, and an awareness of the EU view of the global context would not go amiss, as the current draft text unashamedly says: "Proposals should strengthen the leading role of the EU in clinical research preparedness for future epidemics and pandemics."

The topic is linked to the concept of the European clinical trial networks, which was developed in the context of the COVID-19 pandemic, and currently encompasses a network for COVID therapeutic trials and a network for COVID vaccine trials. In addition, the EU recently gave a new formal status to a European clinical research network that had been in development since before the pandemic. The leaked draft contains plans for backing and sustaining European clinical trial networks for pandemic preparedness and response "through well-established coordination mechanisms between EU adaptive platform trials." That would include fostering a trusted environment for the exchange of trial plans, challenges, and early findings.

Proposals should consider the coordination of adaptive platform trials addressing diverse trial target populations (such as primary care or hospitalized patients) as well as different possible medical countermeasures (including therapeutics and vaccines), within or across networks, which could include performance study plans for diagnostics, says the leaked draft. Connections with relevant initiatives such as the Coalition for Epidemic Preparedness Innovations or the World Health Organization should also be considered in any proposals.

More specific areas of clinical trials are also covered in the draft plans. They include support—in the millions of dollars per project—for developers of combined ATMPs, as part of an overall bid to unlock "the full potential of new tools, technologies, and digital solutions for a healthy society." The project funding would be available for development of ATMPs with one or more medical devices in which the cellular or tissue part contains either viable cells or tissues, or non-viable cells or tissues liable for exerting the primary action on the human body. Research should focus on Phase II clinical trials and above on products in advanced stages of clinical development that have already completed safety studies and where the technologies are ready to undergo interventional clinical trials in patients or end users for assessing the usability and clinical performance. Where the technologies have demonstrable safety and performance profiles, they could also benefit it they are ready to undergo clinical validation for inclusion into guidelines for specific clinical pathways.

The combined ATMPs addressed should be more effective than current state-of-the-art solutions on the European market owing to improved features like personalization, accuracy, reliability, and usability, and should contribute to long-term sustainability of European health systems by providing faster and more affordable treatment, the draft plan remark optimistically. What the EU is looking for with this support, it says, is to provide innovative treatment options with demonstrated health benefits for unmet medical needs, as well as greater scientific certainty on proposed therapeutic approaches. Again, the EU self-interest gets a look-in: "EU companies should also get a better market position in the field," says the draft.

Proposals are likely to be invited on innovative ATMP treatments for any medical condition that are ready to be assessed for clinical efficacy in terms of performance and benefit in a specific indication on a large number of patient cohorts. Products for rare diseases and products with already existing market solutions would not be eligible for this topic.

Europe's Horizon research support stretches widely across areas as diverse as environment and energy, but health has inevitably risen up the agenda in the wake of the coronavirus pandemic, and the move toward coordinating health research and innovation among European countries is gaining strength. The aims are not just to find new ways to prevent diseases and develop better diagnostics and more effective therapies, but to use personalized medicine approaches and promote the take up of innovative health technologies.

View from Brussels

Leaked draft gives glimpse into potential new research proposals as part of the EU’s Horizon program.


Promises of New Support—in Cash, Not Just Comments—for European Clinical Trials

Congressional leaders are proposing significant changes in FDA’s accelerated approval (AA) pathway for expedited development of important new therapies to address critical health conditions. The AA program has long faced criticism due to sponsor delays in conducting required post-approval studies to confirm clinical benefit. Moreover, FDA’s surprise decision last year to approve Biogen’s controversial Alzheimer’s treatment Aduhelm under the accelerated process has focused attention on the risks, benefits, and possible reforms to the program.

These issues have moved to center stage as Congress begins consideration of a host of proposals for revising and improving policies related to drug development and regulation for possible inclusion in broader legislation to reauthorize FDA user fees. The legislative process began with a hearing March 17 before the House Energy & Commerce Health subcommittee. The panel reviewed more than 20 reform proposals that seek to expand diversity in clinical trials, to encourage domestic drug manufacturing, and to support development of generic drugs, biosimilars, antibiotics, and orphan drugs. And the Cures 2.0 Act furthers ongoing initiatives in data collection and clinical trial design to accelerate the discovery and development of new treatments.

A main focus was on measures to reform the AA process by requiring sponsors to conduct and complete confirmatory studies and to make it easier for FDA to remove those drugs from market that fail to meet post-approval commitments. E&C chairman Frank Pallone (D-NJ) led the debate by sponsoring a bill that requires post-approval studies to be underway at time of approval, not just designed and agreed-on by FDA, and for sponsors to provide frequent updates on the status of these studies. The bill also expedites procedures for withdrawing FDA approval for drugs that don’t meet agreed study timelines and, most notable, establishes a five-year timeframe for automatic expiration of an early approval for drugs that fail to confirm efficacy through post-approval studies.

Yet, the Pallone bill raises questions about whether a requirement to begin confirmatory studies prior to approval will discourage or delay accelerated approvals, particularly for small firms with limited resources to support ongoing clinical research programs without a marketed product. And patient advocates fear that such requirements would delay access to needed therapies. However, there’s broad support for policies to make it easier for FDA to remove products from the market when confirmatory studies don’t support initial indications.

As the AA debate has moved to center stage, FDA officials and reviewers continue to examine the value of the program and where reform is needed. At a forum held March 11 by the Regan-Udall Foundation for the FDA, staffers at the Center for Drug Evaluation and Research (CDER) reviewed the 30-year history of the initiative, its benefits, and challenges.

 CDER Principal Deputy Director Jacqueline Corrigan-Curay reported that there have been over 300 accelerated approvals through the end of 2021 for conditions with no approved therapy and where a sponsor can identify a surrogate or intermediate endpoint that permits shorter, smaller clinical trials able to predict likely clinical benefit. While the program was launched in the 1990s to provide faster access to protease inhibitors to treat HIV/AIDS, the explosion in cancer research and identification of surrogate endpoints likely to predict benefit from oncology therapies has greatly increased AAs for cancer treatments—from 18 in 1992-2002 to 112 for the 2013-2022 period. Oncology AAs may be based on tumor shrinkage and studied through single-arm trials that provide earlier measurement of effect, explained Guatam Mehta, medical officer in CDER’s Division of Oncology 2.

Kevin Fain, senior policy advisor in CDER’s Office of New Drug Policy, noted that AA trials must provide substantial evidence that benefits outweigh risks, but that the program allows some “uncertainty as to the relation of surrogate to clinical benefit.” Confirmatory trials are important for addressing that uncertainty and should be underway at time of approval. Corrigan-Curay acknowledged that once a new drug is on the market, sponsors find it difficult to identify patients willing to enter confirmatory studies.

Measures being mulled to reform the AA process and address public concerns around its risk-benefit payoff.

Applied Clinical Trials-04-01-2022