Points of View The Latest Trends in Patient Reported Outcome (PRO) - Survey and Analysis Using Clinical Trial Registration Database

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Akiko Yoshida, Senior Researcher, Pharmaceutical Industry Policy Institute

1. Introduction

Patient Reported Outcome (PRO) is one of the clinical outcomes. SF-36 and EQ-5D are comprehensive measures, and VAS used for pain and WOMAC used for arthritis and back pain are representative examples of disease- and symptom-specific measures. This is a method of evaluation in which patients make their own judgments about symptoms and quality of life, with no intervention by physicians or others. It is applicable to diseases in which changes in the patient's own symptoms and impressions are important, but not to all diseases. 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. 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 meaningful1).

In addition, as described in the "Latest Trends in Patient and Public Involvement (PPI)" section of this Policy Research Institute News, in September 2021, the PMDA issued the "Pharmaceuticals and Medical Devices Agency Patient Involvement Guidance" ("Patient Involvement Guidance") 2). The Guidance states that PROs are "a useful tool for evaluating patient benefits in the review process" and that "their utilization contributes to the efficient development of drugs and other products whose clinical significance is supported by patients. Therefore, it is expected that the number of applications for approval that include PROs as part of the evaluation items will increase in Japan in the future.

Against this background, it is assumed that PROs have been attracting more and more attention in recent years. In this paper, we report the results of a survey and analysis using the Clinical Trials.gov clinical trial registry database (Clinical Trials.gov) to determine the latest trends in the use of PRO-related information in the evaluation of drugs in clinical trials. 3) will be analyzed and reported in comparison with the data from the previous 10 years.

2. Methodology

ClinicalTrials.gov, one of the leading global clinical trial registration databases, was used to investigate and analyze the extent to which clinical trials related to PRO are being conducted and planned4). The search conditions in the database were as follows.

  1. a )
    Newly enrolled study protocols from January 1, 2012 to December 31, 2021 that are Interventional Studies (Interventional Studies) and that describe Drug or Biological as the subject of the intervention (excluding Device, Behavior, Radiation, etc.). (Excluding Device, Behavior, Radiation, etc.)
  2. b )
    The search terms that may be relevant to PRO are Patient Reported, Patient self-reported, Patient Handling Questionnaire, and Patient Satisfaction, and one of these terms must be listed in the outcome measures (e.g., Outcome Measures). Outcome Measures).
  • Note )
    This search condition is limited in its comprehensiveness because it does not specifically define and search all PRO evaluation tools (VAS, EQ-5D, etc.). It should also be noted that trials that only used expressions such as "direct evaluation" or "patient satisfaction" as a description of evaluation methods (which do not correspond to the original PROs) were also extracted as PRO-related clinical trials.

Table 1 Number of PRO-related clinical trials and total clinical trials covered

3. 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 eligible clinical trials") extracted by the search condition a) was 115,016 (109,294 trials, 10-year data from 3 years ago are shown in parentheses). Among them, 4,902 trials (3,265 trials) were hit by the search condition b) (hereafter referred to as PRO-related clinical trials) (Table 1). The number of PRO-related clinical trials has doubled over the past five years, and the ratio of the number of PRO-related clinical trials to the total number of eligible clinical trials has increased even more than three years ago.

Figure 1 Number of PRO-related clinical trials and percentage of total clinical trials covered, year by year

In addition, the annual trend shows that unlike three years ago, when the number of PRO-related clinical trials tended to increase steadily, from 2019 to 2021, the number of PRO-related clinical trials remained almost flat and the proportion of PRO-related clinical trials seemed to have declined slightly (Figure 1). (Figure 1) Although it is difficult to generalize, this period coincided with the COVID-19 epidemic, and it is possible that the initiation of new clinical trials or the suspension or interruption of ongoing clinical trials may have affected the total number of clinical trials and the number of PRO-related clinical trials.

Figure 2 Number of PRO-related clinical trials by region (5-year comparison)

4. By region

Figure 2 shows the changes by region. Comparing the five-year period before and after, the number of PRO-related clinical trials has increased in all regions, with Japan's increase being 1.8 times (1.5 times) that of Europe and the U.S.

Figure 3 shows a comparison of the volume of PRO-related clinical trials (left) and the total number of targeted clinical trials (right) (over a 10-year period). The number of PRO-related clinical trials in Japan is still small compared to other regions, but this can be attributed to the number of total eligible clinical trials.

Figure 3 Number of PRO-related clinical trials (left) vs. volume of total clinical trials covered (right) (10-year comparison)

Table 2 Number of PRO-related Clinical Trials by Disease Category (Top 10 years, 10 categories)

5. By disease category

The number of PRO-related clinical trials by disease category is shown below, along with a comparison of the top 10 categories with the highest number of PRO-related clinical trials in the last 10 years with the 10-year data from three years ago, and a change in ranking. (Table 2) Growth is seen in musculoskeletal and respiratory diseases, and infectious diseases are newly ranked in the top 10 categories. The growth in the number of PRO-related clinical trials in respiratory diseases and infectious diseases may also be related to the COVID-19 epidemic.

  • Note )
    The disease categories are based on ClinicalTrials.gov's own categories (22 categories in this survey), and it should be noted that the number of trials is duplicated when a trial belongs to multiple disease categories, and that the names of the categories are not necessarily the same as those used three years ago. It should be noted that the number of trials is not necessarily the same as the name of the category three years ago.

6. By Trial Phase

Finally, the number of PRO-related clinical trials by study phase is presented below. First, the ratio of the number of PRO-related clinical trials to the total number of eligible clinical trials in each phase was highest in phase 3, followed by phase 4 (Table 3). This is the same trend as three years ago.

Next, a five-year comparison of the percentage of PRO-related clinical trials shows that the percentage increased in the last five years in all phases (Table 4, Figure 4). The proportion of PRO-related clinical trials in the last 5 years in phase 3 exceeded 7%.

Table 3 Number and Percentage of PRO-related Clinical Trials by Phase

Table 4 Number and Percentage of PRO-related Clinical Trials by Phase (5-year comparison)

Figure 4 Number and Percentage of PRO-related Clinical Trials by Phase (5-year comparison)

7. Summary

We investigated and analyzed the extent to which PRO-related information is increasingly used in the evaluation of drugs in clinical trials over the last 10 years. the prevalence of COVID-19 in countries around the world since early 2020 may have influenced the number of PRO-related clinical trials, the total number of clinical trials covered, the proportion of such trials, the disease categories, etc., may have been affected. However, looking at the most recent five years, the number of PRO-related clinical trials increased in the U.S., Europe, Japan, and East Asia in the current extraction. Considering that the term PRO itself was not used very often in the past, it can be inferred that the increase in the number of PRO-related clinical trials is partly due to the more frequent use of PRO-related terms, but it can be said that attention to PROs is increasing.

8. Conclusion

In the future, it can be assumed that the number of applications for approval that include the results of clinical trials with PROs as part of the endpoints will increase in Japan. In addition, the Patient Involvement Guidance states that "the handling of PROs will be examined from the perspective of their actual use in Japan and overseas," and from this perspective, we should continue to pay attention to the future trends of PROs in Japan and overseas.

In Research Paper Series No. 64 (March 2015), Kobayashi had identified Japan's substantial lag in understanding of the concept of PROs compared to Europe and the United States and the lack of guidelines and guidance for validating PROs as essential issues in Japan. Subsequently, however, efforts have been made to standardize each stage of clinical research using PROs (selection of scales, study design, statistical analysis, reporting of results, etc.) in the same manner as clinical research using other outcomes5). In Japan, it is expected that the regulatory authorities will soon develop guidance for PROs, and we hope that this, coupled with the development of the environment and systems and the results of such studies, will lead to a deeper understanding of the concept of PROs.

  • 1) Number of reports and countries from which data was obtained
    Pharmaceutical and Industrial Policy Research Institute, "Study on the Application of Patient Reported Outcome to New Drug Development with the Promotion of Patient-Centered," Research Paper Series No. 64 (March 2015)
  • 2)
    PMDA Patient Involvement Study Working Group, "Pharmaceuticals and Medical Devices Agency Patient Involvement Guidance (Reference date: 2021/1/21)
  • 3)
    Pharmaceutical and Industrial Policy Research Institute, "The Latest Trends in Patient Reported Outcome (PRO) - Survey and Analysis Using the Clinical Trial Registry Database," Policy Research Institute News No. 57 (July 2019), January 1, 2009 to 2018. 10-year data retrieved as of May 21, 2019 through December 31, 2019.
  • 4)
    The study was based on data registered on the ClinicalTrials.gov website (reference: https://clinicaltrials.gov/) as of January 12, 2022.
  • 5)
    Takuhiro Yamaguchi et al, "About Patient Reported Outcome (PRO) and PRO-CTCAE," Pharmacia Vol. 54 No. 3 2018 (reference date 1/29/2022).

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