Points of View Recent Developments in Patient-Reported Outcome (PRO) ―Survey and Analysis Using a Clinical Trial Registry Database―

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The Office of Pharmaceutical Industry Research Kumi Yoshino, Principal Investigator
The Office of Pharmaceutical Industry Research Takahiro Shiraishi, Principal Investigator
The Office of Pharmaceutical Industry Research Shinji Tsubakihara, Principal Investigator

Summary

1. Introduction

Patient-Reported Outcome (PRO) is one of the clinical outcomes defined in the FDA ^guidance1) as "a method of assessment in which subjects make their own judgments about their symptoms and quality of life, without any intervention by the physician or any other party. PRO measures can be broadly classified into comprehensive measures that comprehensively assess general health status (e.g., SF-36, EQ-5D) and disease/symptom-specific measures that assess the degree of a specific disease or associated specific symptoms (e.g., VAS for pain, WOMAC for arthritis and low back pain). PROs are for diseases for which the patient's own symptoms and impressions are important, and not all diseases fall under this category ^. It is easy to recall diseases such as "pain," "itchiness," and "drowsiness," for which there is no reliable and appropriate evaluation method other than the patient's own subjectivity, but until now in Japan, PROs have been used passively for such diseases, as if "we have to use" them. In recent years, however, PROs are being actively utilized for diseases that can be evaluated by physicians, but for which direct evaluation by the patient is equally or more ^meaningful3).

In addition, as described in the previous report, "Usage of Patient-Reported Outcome (PRO) from the Perspective of FDA Published Data " ⁴⁾, in September 2021, the PMDA issued the "Pharmaceuticals and Medical Devices Agency Patient Involvement Guidance " ⁵⁾, which states that "PROs should be used to evaluate patient benefits in the review In September 2021, the PMDA issued "Guidance for Patient Involvement in Pharmaceuticals and Medical Devices Agency (PMDA)5) ", which states that "PRO is a useful tool for evaluating the benefits to patients in the review process, and its utilization is considered to contribute to the efficient development of pharmaceuticals and other products whose clinical significance is supported by patients. Under these circumstances, we assume that the number of applications for approval including the results of clinical trials in which PROs are part of the endpoints will increase in Japan, and we have reported on the number of PRO-related clinical trials in past ^{news6, 7)}.

In this report, we conducted a survey and analysis using the Clinical Trials Registry Database (ClinicalTrials.gov) to determine the latest trends in the current use of PRO-related information in the evaluation of drugs in clinical trials. We report on the recent trends, comparing the data with those of two previous reports at OPIR Views and Actions.

Survey Methodology

Using ClinicalTrials.gov, a clinical trial registration database, we surveyed and analyzed the extent to which clinical trials related to PROs are being conducted or ^planned8). ClinicalTrials.gov is a clinical trial registration system operated by the National Institutes of Health (NIH) and other organizations. Although it is a U.S. registration system, it also registers information on clinical trials in which the U.S. does not participate from the perspective of corporate strategy, such as the purpose of information dissemination by each ^company9). The search conditions in the database are as follows.

(a) Interventional studies (study protocols newly registered between January 1, 2009 and December 31, 2023*) that are described as Drug or Biological as the subject of the intervention (excluding Device, Behavior, Radiation, etc.), a') Some of the studies were also conducted if the intervention was described as "Genetic".

(b') Potential PRO-related search terms were Patient Reported, Patient self-reported, Patient Handling Questionnaire, and Patient Satisfaction. Outcome Measures).

(c) Survey by disease category: MeSH (Medical Subject Headings) listed as relevant words in each study were extracted and classified by their super terms C01~C26. The top words were determined based on the Tree ^View10) in the MeSH Browser of the National Library of Medicine website. (d) Phase-specific surveys.

(d) Investigation by Phase: The number and percentage of trials by Phase (Phase 1, Phase 2 (including Phase 1/2), Phase 3 (including Phase 2/3), and Phase 4) registered in ClinicalTrials.gov were investigated. Early phase 1 (previously Phase 1 (trials previously designated as Phase 0) and NA (trials with no FDA-defined phase) were not included in the survey by phase.

e) Surveys by region: Counted by country/region where the study was conducted according to the ClinicalTrials.gov definition. Trials conducted in multiple regions were counted in both (duplicate).

It has been pointed out in a previous OPIR Views and Actionsthat the registration details on ClinicalTrials.gov may change depending on the progress of each clinical trial and other factors, and the possibility of such changes is higher the closer to the date of data ^{acquisition11)}. Therefore, while it was possible to investigate the data for 2024, the most recent data was not included in the survey this time, as it was determined that there were significant concerns about the lack of information. Even for previously reported periods, comparisons of the actual number of clinical trials were made only within the same survey, since the number of total clinical trials and PRO-related clinical trials is likely to have varied depending on the survey period.

Results

3-1. Number of PRO-related clinical trials

The total number of clinical trials (all clinical trials with the same time period and intervention method: hereinafter referred to as "total clinical trials") extracted by the search condition a) was 168,262 in total. Of these, 6,273 trials (hereafter referred to as "PRO-related trials") were identified using the search condition b) (Table 1). When the time period was divided into 5 years, the number of PRO-related clinical trials in the last 5 years increased 3.7 times compared to 10~15 years ago and 1.6 times compared to 5~10 years ago, and the proportion of PRO-related clinical trials in the total clinical trials also increased over time to 1.9%, 3.7%, and 5.1%, respectively.

In addition, we also investigated the search condition a') for the purpose of confirming the trend of PRO-related clinical trials in gene therapy-related trials, as we believe that the number of products related to gene therapy has been increasing in recent years, although we did not investigate this in the past news. The results showed that the total number of trials was 2,398 and the number of PRO-related clinical trials was 77. The percentages of PRO-related clinical trials in the total clinical trials were 1.2%, 2.9%, and 4.6% when the time period was divided into 5 years (Table 2). The same trend as in search condition a) (Drug or Biological) was observed, suggesting that PROs are increasingly being used in gene therapy-related trials, but the impact of the number was judged to be small, and Genetic was not included in subsequent surveys.

Looking at the annual trends, as with the 2019 and 2022 news, there was a trend of almost steady increase through 2019, but from 2020 to 2023, both the number and percentage of PRO-related clinical trials remained almost flat (Figure 1).

3-2. By disease category

Next, we compared the number of PRO-related clinical trials by disease category, broken down by five-year period for the past 10 years, and then compared before and after. Pathological Conditions, Signs and Symptoms had the highest number of trials in both five-year periods, followed by Neoplasms (Figure 2). On the other hand, Musculoskeletal Diseases had the highest percentage of PRO-related clinical trials in both five-year periods, while the categories that ranked first and second in terms of number of trials both had lower rankings (2014-2018 and 2019 -2023, PathologicalConditions, Signs and Symptoms ranked 4th and 7th, respectively, and Neoplasms ranked 15th and 18th, respectively).

3-3. By Trial Phase

The number of PRO-related clinical trials by study Phase is then presented below. First, the ratio of PRO-related clinical trials to total clinical trials in each Phase was highest in Phase 3 (including Phase 2/3), followed by Phase 4 (Figure 3, bar graph). This is the same trend as in the previous two reports.

Next, a five-year comparison of the percentage of PRO-related clinical trials shows that the percentage increased in the most recent five years in all Phases (Figure 3, line graph). Also, the percentage of PRO-related clinical trials in the last 5 years in Phase 3 exceeded 7%, similar to previous OPIR Views and Actionsyears.

3-4. By Country/Region

Finally, changes by country/region are shown in Figure 4. The survey covered the United States, the European countries of the United Kingdom, France, Germany, and Italy, and the East Asian countries and regions of Japan, China, Hong Kong, Taiwan, and Korea. The number of PRO-related clinical trials (Figure 4, bar graph) increased in all countries/regions when compared at intervals of 5 years. In terms of the number of trials in the last 5 years (2019~2023), Japan (208 trials) is lower than the United States (1,808 trials) and European countries (351~382 trials), which have a significantly higher number of trials, but the number of trials in the last 5 years (2019~2023) increased compared to the 5 years (2014~2018). However, the increase in Japan (1.5x [208 studies/141 studies]) was comparable to that of the United States (1.5x [1,808 studies/1,173 studies]) and European countries (1.4x-1.7x [351~382 studies/209~264 studies]). On the other hand, the number of PRO-related clinical trials in China (316 trials) was similar to that of European countries, and the ratio of increase was 3.0-fold, showing a large increase.

As for the ratio of PRO-related clinical trials to total clinical trials (Figure 4, line graph), Japan's ratio was 10.5% over the last five years (2019-2023), which was similar to other countries/regions, while China's ratio was remarkably low at 2.7%.

As shown in Figure 3, the proportion of PRO-related clinical trials is highest in Phase 3, and Phase 3 is also more closely related to drug approval. As a result, the overall percentage was about 5 percentage points higher than in the survey for all Phases (Figure 4), but there was no significant difference in trend among countries/regions, with only China's percentage falling below 10% (for 2019~2023, United States: 12.9% [457 trials/3, 533 trials], Europe 533 trials], European countries: 14.2~16.2%, Japan: 15.2% [159 trials/1,046 trials], China: 7.5% [158 trials/2,117 trials], other East Asia: 13.7~16.7%, not shown).

4. Summary and Discussion

The number of PRO-related clinical trials and their ratio to the total number of clinical trials have been growing steadily in five-year intervals, but the annual trends show a trend of becoming more constant after 2020 (Figure 1). A trend toward constant growth was observed (Figure 1). This period partly coincided with the COVID-19 epidemic, and it is assumed that there were circumstances in which new clinical trials were initiated or ongoing clinical trials were suspended or halted for diseases other than those related to COVID-19. In fact, the PRO-related studies by disease category have been conducted.

In fact, a review of the number of PRO-related clinical trials by disease category shows that during this period, the number of PRO-related clinical trials in the disease categories Infections and Respiratory Tract Diseases, which appear to be related to COVID-19, increased significantly from 2020 onward compared to 2019, while the number of PRO-related clinical trials in the disease categories Infectious Diseases and Respiratory Tract Diseases increased significantly from 2019 onward. While there will be an increase in the categories with the highest number of PRO-related clinical trials, Pathological Conditions, Signs and Symptoms, Neoplasm, and Skin and Connective Tissue Diseases, Nervous System Diseases) and Musculoskeletal Diseases, a category with a high proportion of PRO-related clinical trials, showed scattered periods of decline from 2019 (Supplement 1). Also, the total number of clinical trials in all categories has not grown since 2020 (13,329 in 2020, 13,115 in 2021, 13,093 in 2022, and 12,845 in 2023). Although not included in the survey this time, growth in both the number of PRO-related clinical trials (774 trials) and the total number of clinical trials (13,904 trials) was observed in 2024, suggesting the possibility of a recovery trend in the future, but the possibility of a slowdown in the growth rate of PRO-related clinical trials cannot be denied, However, the possibility that the growth rate of PRO-related clinical trials may be slowing down cannot be ruled out, and future trends will need to be monitored closely.

As for the survey by disease category and trial phase, as mentioned above, no major changes in trends were observed compared to the previous news. However, there was a trend toward an increase in the percentage of PRO-related clinical trials in both disease categories and Phases, indicating an overall increase in interest in PROs. The most notable change in the last five years was in Occupational Diseases, where the proportion of PRO-related clinical trials increased from 0% to 9.5%, the third highest proportion among disease categories (Figure 2). However, the actual number was not high, with 6 PRO-related clinical trials out of 63 total clinical trials. In a disease category where the total number of clinical trials is small, a slight increase or decrease in the number of PRO-related clinical trials may have a large impact on the ratio, and it remains to be seen whether this trend will continue or not.

By country/region, the number of PRO-related clinical trials has been increasing in every country/region over a five-year period (Fig. 4). The United States was the country with the largest number of PRO-related clinical trials, followed by Europe. This may be due to the progress in the development of PRO-related guidance and other environments in the United States and Europe.

In China, the number of PRO-related clinical trials in the last five years was the same as that in Europe, and has been growing rapidly in recent years (Fig. 4). This may be due to the increased interest in PROs and the improvement of the environment, as evidenced by the publication of the "Guidelines for the Application of Patient-Reported Outcomes (PROs) to Clinical Trials of Pharmaceuticals" in January ^202212), in which PROs are considered to be indicators that reflect improvements in patient quality of life and clinical value. On the other hand, the percentage of PRO-related clinical trials itself was notably low and was 3~4 times higher than in other countries/regions (2019~2023: 2.7%, Figure 4), but when limited to Phase 3, the percentage was about 5 points higher as in other countries/regions (2019~2023: 7.5%, no figure), and the gap with other countries/regions narrowed to about 2 times. The gap with other countries/regions also narrowed to about twice as much. These results suggest that the proportion of PRO-related clinical trials in Phase 3 is smaller in China and other countries/regions than in other phases.

In Japan, the percentage of PRO-related clinical trials was similar to that in Europe (Fig. 4), suggesting that the capacity and environment to conduct such trials are in place.

The percentage of PRO-related clinical trials conducted in multiple countries did not differ significantly among countries and regions, including China (Supplemental 2), suggesting that conducting trials in multiple countries may facilitate the adoption of PROs in accordance with countries and regions where PRO awareness is leading. On the other hand, the proportion of PRO-related clinical trials in trials conducted only in a single country varied by country/region (Supplement 3). Various factors could be considered, such as differences in awareness of PROs in each country and region, differences in the environment for PROs and their use for approval, and differences in disease categories in which clinical trials are likely to be conducted in each country and region. In order to further increase the proportion of PRO-related clinical trials in each country/region, increasing the number of trials in multiple countries and considering measures to accelerate the penetration of PRO into trials in a single country would be important factors.

5. Conclusion

The results of the survey conducted in this report indicate that the number and percentage of PRO-related clinical trials are increasing in each country and region, but although the overall PRO utilization rate in Japan is similar to that in the United States and Europe, there are still issues to be addressed, such as the utilization rate in single country trials. In Japan, the Patient Involvement ^{Guidance5) also} states that "the handling of PROs should be considered from the perspective of their actual use in Japan and abroad," and in June 2023, a report entitled "Preparation of PRO Guidelines in Collaboration with Initiatives by Related Academic Societies " ¹³⁾ was issued, suggesting that PROs should be evaluated in clinical trials that include PROs as part of the evaluation items. In June 2023, it was reported that "PRO guidelines will be developed in conjunction with the efforts of related societies "13). We expect the number of PRO-related clinical trials to increase as awareness of PROs is further raised and the environment for their implementation and utilization is improved, and we will continue to monitor the trend closely.

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