Points of View Trends in Outcome Measurement Tools for Digital Therapeutics (DTx) -Survey using Clinical Trial Database

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Junya Tsujii, Senior Researcher, National Institute of Biomedical Innovation Policy

1. Introduction

In the Policy Research Institute News No. 69, the author systematically summarized the various values that digital therapeutics (DTx) can ^bring1). 1) The author systematically categorized the value of DTx into "medical value" and "social value" from the viewpoint of value recipients (Fig. 1). The "medical value" includes the "therapeutic value" of efficacy and safety, and the "supportive value" of optimizing the treatment process in terms of structure and process, improving treatment efficacy, or expanding treatment opportunities and self-management capacity. The "supportive value" is the value provided by elements related to "improving patient-related structures and processes," which is one of the clinical effects (positive care effect) required of the German DiGA (German for digital health application). Elements related to "improvement of patient-related structures and processes" include: (1) coordination of treatment procedures, (2) alignment with guidelines and recognized treatment standards, (3) adherence, (4) promotion of access to treatment, (5) patient safety, (6) health literacy, (7) patient independence, and (8) coping with disease-related difficulties in daily life, (ix) Reduction of treatment-related labor and burden for patients and their relatives.

In order for these values to be evaluated in the reimbursement system, one approach would be to use appropriate outcome measurement tools to quantitatively demonstrate their value. However, the current examples of "supportive value," which is a value unique to DTx, are more limited than those of "therapeutic value," which verifies effectiveness, etc., and it may be difficult to imagine what kind of outcome measurement tool should be used to verify this value. Therefore, this paper focuses on outcome measurement tools that have been used in Germany to "improve patient-related structures and processes" as a way to help quantify "supportive value," and investigates their use in clinical trials using digital technology. It is important to consider not only the quantifiable value established by outcome measurement tools as the value of DTx, but also a system that can consider non-quantifiable value (qualitative value), as NICE in the UK does in its evaluation of medical technology, taking into account the wide-ranging opinions of patient groups, medical experts, and other stakeholders. It will be important to consider a system that can take non-quantifiable values (qualitative values ⁾ into account as ^well2).

2. survey target

Outcome measurement tools that had been used in the validation of "patient-related structural and process improvements" were surveyed for the 47 products registered (full or provisional registration, excluding deregistered products) in the German DiGA Directory as of May 24, ²⁰²³³ ) (Table 1). Of the nine aforementioned value elements, the current registered products included the following examples: alignment with guidelines and recognized treatment standards: 1 product; health literacy: 2 products; patient independence: 3 products; coping with disease-related difficulties in daily life: 2 products; and reducing treatment-related effort and burden on patients and relatives: 1 product.

3. survey methodology

3-1. clinical trial database used 3-2.

The survey was conducted using two clinical trial databases: ClinicalTrials.gov provided by the U.S. National Library of Medicine and others, and the German Clinical Trials Register (DRKS) provided by the German Federal Institute for Pharmaceuticals and Medical Devices (BfArM). (DRKS), provided by the German Federal Institute for Drugs and Medical Devices (BfArM) (all data as of May 2023). The search criteria for clinical trials were as follows: trials with interventions using digital technology (e.g., mobile applications) were extracted from the descriptions (if there were trials with overlapping contents in the two databases, only trials with earlier registration dates were counted). Please note that this study is not a search that specifically specifies all outcome measurement tools related to supportive value, and thus has limitations in comprehensiveness.

3-2. search criteria

The search criteria for each of the clinical trial databases were as follows. The disease areas covered are based on the ICD-10 (2013 edition) ^{classification4)}.

ClinicalTrials.gov

German Clinical Trials Register

4. results

4-1. alignment with guidelines and recognized treatment standards

For alignment with guidelines and recognized treatment standards, the "European Heart Failure Self-Care Behaviour Scale (EHFScBS) ⁵⁾ (degree of self-care behavior in heart failure patients) was used as an outcome measurement tool in some cases.

The survey results showed that there were not many trials that included the "European Heart Failure Self-Care Behaviour Scale" as an outcome (28), but there was a slight increasing trend after ²⁰²¹⁶⁾ (Figure 2, all of them with heart failure as the target disease). In terms of the positioning of the outcome measures, there were 12 trials that included the primary outcome and 13 trials that included the secondary outcome, which was almost the same number. (There were also three trials with Other outcomes.

4-2. health literacy

For health literacy, the Depression Literacy ^scale7,8) (ability to recognize depression and make informed decisions about treatment) and the European Health Literacy Survey Questionnaire (HLS-EU-Q) ⁹⁾ (ability to access, understand, evaluate, and apply information in health care, disease prevention, and health promotion) as outcome measurement ^tools10).

The survey revealed that only four trials (two in 2021 and two in 2022) included the "Depression Literacy scale" as an outcome in only a few ^cases11). There were also not many clinical trials that included the "European Health Literacy Survey Questionnaire" as an outcome (24), but the number of trials per year has been slightly increasing since ^202112) (Figure 3). In addition, many trials (17 out of 24 trials) were set as Secondary outcome in terms of measurement items. In terms of target disease areas, the use of the questionnaire in endocrinology, nutrition and metabolism, cardiovascular system, and neoplasms was high, and the improvement of health literacy was verified in diseases that require relatively long-term treatment or have a high impact on life, such as diabetes, obesity, cardiac diseases (including rehabilitation), and cancer. No significant trend was observed in the number of disease areas covered by year.

4-3. patient independence

For patient independence, the Anxiety Control Questionnaire (ACQ) ¹³⁾ (perception of control related to depressive and anxiety symptoms), the Alcohol Abstinence Self-Efficacy Questionnaire (AASE) ^14, (Alcohol Abstinence Self-Efficacy Questionnaire (AASE)14, ¹⁵⁾ (individuals' confidence in their ability to avoid drinking in certain situations), and the Patient Activation Measure (PAM) ^{16, 17)} (knowledge, skills, and confidence in managing their own health and wellness) were identified as examples of use.

The results of the survey showed that 6 clinical ^trials18) included the "Anxiety Control Questionnaire" as an outcome and 18 trials included the "Alcohol Abstinence Self-Efficacy Questionnaire" as an ^outcome19), indicating limited use. 19), indicating that its use was limited.

On the other hand, there were 187 clinical trials that included the "Patient Activation Measure" as an outcome, showing an increasing trend over ^time20) (Figure 4). In addition, approximately 70% of the clinical trials were set as Secondary outcomes. As in the case of health literacy, the target disease areas were cardiovascular, endocrine, nutrition and metabolism, and neoplasm, and many of the trials focused on improving self-efficacy to promote treatment of chronic diseases such as hypertension, diabetes, and obesity, to strengthen patients' self-management against heart disease, stroke, and cancer, and to prevent serious illness and recurrence of such diseases. No significant trend was observed in the number of disease areas covered by year.

4-4. coping with disease-related difficulties in daily life

For coping with disease-related difficulties in daily life, the Bochum Change Questionnaire-200021 ⁾ (treatment-related mood and behavior changes) and the Work Productivity and Activity Impairment Questionnaire ( (WPAI) ^{22, 23)} (work productivity and impairment in daily life) as outcome measurement tools. It should be noted that in Policy Research Institute News No. 69, "Considering the Value of Digital Therapeutics (DTx), " ¹⁾ the improvement of patient productivity is organized as one of the "social values.

The survey revealed that only two clinical trials included the "Bochum Change Questionnaire-2000" as an ^outcome24).

On the other hand, 75 clinical trials included the "Work Productivity and Activity Impairment Questionnaire" as an outcome, showing a slight increase in the last five ^years25) (Figure 5). In addition, approximately 70% of the clinical trials included the "Work Productivity and Activity Impairment Questionnaire" as a secondary outcome. In terms of target disease areas, musculoskeletal and connective tissue, neurological, and gastrointestinal diseases were the most common, and WPAI tended to be used in diseases with chronic pain and persistent subjective symptoms, such as various types of arthritis, body pain (neck pain, back pain, etc.), insomnia, irritable bowel syndrome, and inflammatory bowel disease. In addition, the number of disease areas covered by WPAI by year shows that in addition to the above disease areas, WPAI has recently been used in studies for mental and behavioral disorders such as depression, etc. As for the type of WPAI, WPAI-GH (General Health), which is commonly used for a variety of diseases, was most commonly used, but WPAI-MS (multiple sclerosis) and WPAI Multiple Sclerosis), WPAI-UC (Ulcerative Colitis), WPAI-ASTMA (Asthma), and other tools optimized for specific diseases were also used.

4-5. reduction of treatment-related effort and burden on patients and relatives

For the reduction of treatment-related labor and burden of patients and relatives, the "Brief Symptom Inventory (BSI) ²⁶⁾ " (the degree of general psychological distress of people with psychological problems) was used as an outcome measurement tool in one case.

There were 103 clinical trials that included the Brief Symptom Inventory as an outcome, with a slight increase in the last five ^years27) (Figure 6). Since the Brief Symptom Inventory is a measure of psychological distress, the majority of the target disease areas were mental and behavioral disorders, but there was a slight increase in psychological distress associated with cancer, brain injury, inflammatory bowel disease, etc. (Fig. 6). However, there were some studies in which the Brief Symptom Inventory was used as a measure of psychological distress associated with cancer, brain injury, inflammatory bowel disease, and other disorders. There was no significant trend in the number of disease areas covered by year.

Development of outcome measurement tools

The outcome measurement tools included in this survey were not developed specifically for DTx. For example, the European Health Literacy Survey Questionnaire (HLS-EU-Q) was launched by a consortium of eight EU member states (Austria, Bulgaria, Germany, Greece, Ireland, the Netherlands, Poland, Spain) to survey national health literacy in Europe. The HLS-EU-Q is a measurement tool developed by the European Health Literacy Project (HLS-EU), a consortium of eight EU member states (Austria, Bulgaria, Germany, Greece, Ireland, the Netherlands, Poland, and Spain) to survey the health literacy of citizens in ^Europe9). Currently, the HLS-EU-Q is being translated and used in countries around the world other than Europe, and the reliability and validity of the Japanese version is being verified in ^Japan28).

The Patient Activation Measure was developed by Dr. Judith Hibbard and colleagues at the University of Oregon over 15 years ago, and has been used in over 800 peer-reviewed ^{studies16,29)}.

The Work Productivity and Activity Impairment Questionnaire (WPAI) was developed by Dr. Reilly and colleagues to measure the impact of work and daily activities on productivity and has long been used in drug ^{development2, 22)}. In addition, as mentioned in section 4, the WPAI is developing a variety of measurement tools for specific diseases. Currently, more than 10 disease-specific WPAIs have been ^developed22), and the International Headache Society has proposed the use of a migraine-specific WPAI as a pharmacoeconomic endpoint for chronic ^migraine30). A wide range of researchers, not only from academia but also from pharmaceutical companies and medical institutions (research centers), have been involved in the development of these ^{indicators31, 32, 33).}

As described above, various members are involved in the development of outcome measurement tools, sometimes collaborating across national and positional boundaries. Currently, there may be little need for DTx-specific outcome measurement tools, but in the future, as technology evolves, etc., there will be occasions when new outcome measurement tools that take into account the characteristics of DTx will need to be developed. On the other hand, many DTx developers are start-ups, and it is not realistic for such companies to develop new outcome measurement tools or to validate translated versions of overseas measurement tools for their own clinical trials, considering the resources and financial burden involved. In order to promote DTx development in Japan, it may be important to promote the development of outcome measurement tools through collaboration among industry, government, and academia.

6. summary

In this paper, we focus on outcome measurement tools that have been used for "improving patient-related structures and processes" in Germany, and summarize their use in clinical trials involving digital technology, as a way to help quantify "supportive value. The survey included outcome measures such as the "European Health Literacy Survey Questionnaire" as a measure of health literacy, the "Patient Activation Measure" as a measure of patient independence, and the "Brief Symptom Inventory" as a measure of psychological distress. Inventory, a measure of psychological distress. Several of these have seen increasing use in clinical trials in recent years. One may speculate that this is due to the increase in the number of clinical trials using digital technology ^itself34), but it could also be said that the various values of DTx are being recognized among developers and their validation is becoming more widespread.

We hope that the information in this report will help in quantifying the value required of DTx developers.

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