Addressing Concerns Raised in Health Affairs Article About PDTs

We recently read the Health Affairs article titled "Studies of Prescription Digital Therapeutics Often Lack Rigor and Inclusivity" by Anika Kumar et al. While we appreciate the effort put into the study, the Digital Therapeutic Alliance would like to offer some clarifications and considerations that may contribute to a deeper understanding of the digital therapeutics (DTx) landscape. We have grouped them into 10 points.

For background, a digital therapeutic is health software intended to treat or alleviate a disease, disorder, condition, or injury by generating and delivering a medical intervention that has a demonstrable positive therapeutic impact on a patient’s health (ISO/TR 11147). Digital therapeutics may be stand-alone software or may be combined with wearables and devices. Accessing digital therapeutics encompasses various avenues, with prescription serving as merely one.

1. Premarket approval and risk assessment

The study begins by discussing premarket approval (PMA) for high-risk devices, asserting that no DTx has undergone the "FDA's most rigorous review pathway."It is crucial to note that none of the DTx products are inherently high risk, and in fact, FDA would certainly reject the PMA pathway for a DTx. The PMA pathway, as defined by the FDA, is only used for Class III products, which are devices that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury, such as pacemakers.The study indicates that 65% were authorized through the 510(k) pathway and 35% through Denovo, suggesting a predominantly low-risk profile. Therefore, the absence of pre-market approval (PMA pathway) does not imply a lack of rigor for DTx products.

2. Blinding

Conducting a sham (or placebo) study with cognitive behavioral therapy (CBT) or digital therapeutic products pose inherent challenges. Unlike drug trials where a placebo product can be administered effectively, creating a credible placebo for psychological interventions like CBT is complex due to the nature of the therapy. Additionally, replicating the therapeutic effect without the active elements of CBT makes blinding difficult.

In the case of many digital therapeutic products, designing a sham group that mimics the user experience without delivering the intended therapeutic content is not possible since the clinical outcomes often rely on specific, tailored interventions. Comparisons to treatment as usual (TAU) can provide robust evidence, and the FDA's clinical guidelines for DTx recognize the unique nature of these interventions.

3. Study design

Innovations like decentralized and virtual trials address logistical challenges while ensuring diverse samples, which is crucial, especially with nationwide recruitment.The emphasis should be on the appropriateness of the chosen study design for the research question.

In the article, the authors mention that these DTx companies are well-funded and could easily fund large-scale clinical trials. But we want to highlight that the vast majority of DTx companies are independent startups. Many are in their seed - Series A rounds of funding and have generally raised between $5-7MM. DTx companies do not have the money nor the resources of pharmaceutical or medical device companies. As the adoption and revenue of prescription digital therapeutics continue to rise, we anticipate an accompanying enhancement in study designs, reflecting a commitment to robust and rigorous research methodologies.

4. Digital Therapeutics Alliance's product library

While we appreciate the use of DTA’s Product library, the limitations of the Product Library in listing all trials from manufacturers should be acknowledged. DTA has more than 100 member companies, listing products in the DTA library is voluntary and there is a restriction to listing only three clinical trials for each company. The current library includes just 16 companies and 22 products. Of these products, seven are not available in the United States. These restrictions can skew the perception of the breadth of evidence supporting DTx.

5. Language proficiency and global adoption

English proficiency as a baseline requirement is common among U.S.-based startups. However, it's essential to recognize that adoption into more languages will likely grow in tandem with increased U.S adoption and increased funding by investors based on the early results of clinical trials. Limited language availability at this stage should be understood in the context of evolving market dynamics.

6. Strength of evidence in PDT studies

The strength of evidence is clearly shown in Exhibit 4 of the Health Affairs article, but the interpretation presented in the article implies this is negative. In fact, this table shows:

• 90% of PDTs having randomized clinical trials
• 60% were blinded
• 100% meeting a clinical primary endpoint
• 75% have multicenter studies

We find this to be a positive for the PDTs reviewed since it demonstrates the robustness of the evidence supporting DTx.

7. Long-term follow-up data and real-world evidence

The study's authors express concern about the lack of long-term follow-up data for DTx, impacting payer hesitancy. Many PDTs incorporate built-in mechanisms within their apps to provide real-world patient reported outcome data, which can address this concern and contribute to ongoing evidence generation. This feature addresses concerns about the lack of long-term data and should be recognized as a strength rather than a limitation. Further, many DTx companies follow patients in their clinical trials out to at least one year to demonstrate long term benefits, and often payers that incorporate DTx products require the manufacturer to follow the clinical outcomes of patients as well as costs for at least one year. Lastly, the primary purpose of long term follow-up data is to determine safety and measure adverse events over a longer period of time, given the non-invasive nature of DTx products the need to measure this over the long term is not as relevant.

8. Diversity in clinical trials

Limited diversity and inclusion in clinical trials are acknowledged issues across the healthcare industry. It's crucial to recognize that this challenge is not unique to DTx trials and is a broader concern within the field of clinical research including pharmaceuticals and medical devices.(Turner et al., 2022, Khan et al., 2020; Lolic et al., 2021). When conducting clinical trials with payers, it is often the case that they will not provide access to their Medicare population, and access to Medicaid patients is even more difficult, thus follow-on studies and real-world data collection is required. This is achieved in the real-world utilization of DTx as they are often adopted across a diverse population and measured using the robust data gathering platforms most DTx products have designed. Furthermore, DTx products have the ability to demonstrate clinical outcomes and adherence rates broken out by line of business for a payer on a monthly basis, which is unique to healthcare.

9. Industry advocacy for strong clinical data

While there is room for research improvement, the DTx industry has openly advocated for strong clinical data, emphasizing the commitment to rigorous research standards (e.g., Espie, Torous & Brennan., 2022Espie et al., 2018) DTA Value GuideSetting the Stage for a Fit-For-Purpose DTx Evidentiary Standard

10. Study limitations and dialogue invitation

The authors mention that one study limitation is that they may not have identified all PDT products or studies due to the absence of a uniform review pathway. We are keen to engage in a constructive dialogue about the data and would appreciate the opportunity to discuss the specific list of PDTs reviewed in the study. Furthermore, we would like to highlight some PDTs with extensive data published in peer-reviewed journals

While continuous improvement is essential, it's equally important to strike a balance that does not stifle innovation in a field that has the potential to transform healthcare. It is equally crucial to acknowledge the robust evidence supporting digital therapeutics.

Our objective is not to diminish the evidentiary requirements but rather to ensure that the evaluation process aligns appropriately with the unique nature of DTx. This study underscores crucial considerations, yet a more profound comprehension of the DTx landscape is essential for accurate interpretation.

We look forward to the opportunity for further discussion and collaboration to advance the field of digital therapeutics.

The Digital Therapeutics Alliance (DTA) is a global non-profit organization that advocates for the adoption and integration of digital therapeutics into mainstream healthcare. DTA provides a platform for collaboration among industry stakeholders, including healthcare providers, technology developers, and regulatory bodies. We focus on establishing industry standards, promoting research, and advancing the understanding of digital therapeutics' efficacy and value in treating various medical conditions. DTA aims to drive awareness, credibility, and accessibility of digital therapeutics. DTA seeks to ensure the responsible and effective use of digital therapeutics in improving patient outcomes.