Points of View Patient-Reported Outcome (PRO) usage based on FDA published data
Patient-Reported Outcome (PRO) Usage Status

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Shinji Tsubakihara, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Takahiro Shiraishi, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Kyumi Yoshino, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

SUMMARY

1. Introduction

The "Policy Proposal 2025" and "Industrial Vision 2035" published by the Japan Pharmaceutical Manufacturers Association (JPMA) in 2025 recognize that it is extremely important to encourage patients to actively participate in research in order to achieve drug innovation that can better meet the needs of individual patients. The Pharmaceutical Manufacturers Association of Japan (PMAJ) aims to realize patient- and public-involved drug discovery by shifting from the perspective of producers to that of patients and citizens and promoting "Patient and Public Involvement/Engagement (PPI/E) and Co-creation (co-creation) with patients". ¹⁾. One of the methods is the use of "Patient-Reported Outcome (PRO)" and "Real World Data (RWD)". PRO is a Clinical Outcome Assessment (COA) measure based on information reported directly by patients themselves regarding their health status, defined by the FDA as "any report of a patient's health status obtained directly from the patient, without interpretation by the clinician or anyone else ^{.(FDA, 2006)}.

The concepts measured or assessed by PROs include: 1) subjective sensations and experiences that only the patient can recognize, such as pain, itching, shortness of breath, etc.; 2) any type of function or activity in the patient's daily life; 3) patient satisfaction or dissatisfaction with the treatment or functionality provided by medical technology; and 4) the degree to which multiple symptoms of a disease affect daily life. ⁽ 4 ⁾ The degree of impact on daily life caused by multiple symptoms of the ^disease2).

As a recent development regarding the promotion of patient participation in drug development, the government released an interim summary of "Future Direction for the Promotion of Clinical Research and Clinical Trials" by the Clinical Research Committee of the Health Sciences Council in 2019, and one of the basic ideas for the promotion of clinical research and clinical trials is to "promote understanding and participation of the public and patients. ^3). In the same year, the Japan Agency for Medical Research and Development (AMED) published the "Patient and Public Involvement (PPI) Guidebook" (Figure 1) after conducting a "Survey on Trends in Patient and Public Involvement in Clinical Research, etc. " ⁴⁾. The definition of PPI in this guidebook is defined by AMED as "the practice of researchers referring to the findings of patients and citizens as part of the medical research and clinical trial process," and the guidebook was created to promote understanding among both researchers and patients/citizens regarding the significance of incorporating the perspectives of patients/citizens into medical research and clinical trials. The important point here is that "the "experiential knowledge" of patients/citizens may enable us to find new research possibilities for issues that cannot be solved by researchers' "specialized knowledge" and for viewpoints that cannot be found. In 2021, the Pharmaceuticals and Medical Devices Agency (PMDA) published the "PMDA Patient Involvement Guidance", ⁵⁾ which provides guidelines for activities to promote patient involvement that should be referred to by PMDA and its officers and employees. The goal is to actively collect patients' opinions and realize a "Patient First" approach.

In academia, a systematic study of PROs was initiated in 2020 by the Research Group on Administrative Policy of the Ministry of Health, Labour and Welfare, and in June 2023, "Creation of PRO Guidelines in Collaboration with Initiatives of Related Academic Societies" was reported as a research ^result6). The report states that in Europe and the U.S., guidelines on the use of PROs in clinical trials and clinical practice have been issued by regulatory authorities since around 2005, but that in Japan, despite the fact that basic and applied research on PROs and quality of life assessment has been conducted as much as overseas, no guidance on the use of PROs has been published. The study group also noted that Japan has lagged behind Europe and the U.S. by 20 years in recognizing the importance of utilizing the results of quantitative assessments of subjective health perspectives as evidence in medical care. The group speculates that the main reasons for this are that Japan's awareness of human rights is not "necessarily" higher than that of advanced Western countries, and that the general public, including patients, does not take a high degree of autonomy in medical decision-making. The results of this research were later published as the "Patient-Reported Outcomes (PRO) Evaluation Special Page," the first public guidance for implementing PROs in clinical research in ^Japan7). 7) This site serves as a guideline for the use of PROs in efficacy and safety evaluations, which are expected to be implemented more and more in Japan as the number of global clinical trials of new drugs increases. This website not only provides guidance on the use of PROs, but also comprehensively describes the transition of the concept of PROs in Europe and the United States, the transition of guidance on the use of PROs, and the flow of PRO scale development, etc. For details, please refer to this website.

In Japan, industry, government, and academia are promoting active patient participation in drug development and the use of PROs, and in order to understand the actual use of PROs in drug development in recent years, the U.S. FDA published in 2021 the "CLINICAL OUTCOME ASSESSMENT (hereinafter referred to as "COA COMPENDIUM"; Figure 2), published by the U.S. FDA in 2021, ⁸⁾ and analyze the position and significance of PROs in the actual use of COAs in each disease area. Prior to this, an overview of the background of the publication of this document is provided.

In 2009, the FDA published "Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims" to provide guidance to pharmaceutical companies and other drug developers on the use of COAs in the development of medical products. In 2009, the FDA published "Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims," a set of guidelines for pharmaceutical companies and other drug developers regarding the use of PROs in clinical trials for the purpose of regulatory ^approval2). Subsequently, in 2016, the United States enacted into law "the 21st Century Cures Act" (Cures Act, 21st Century Cures Act), which aims to promote innovation in the medical field by expediting the development and approval process of drugs and medical devices, increasing research funding, and improving mental health ^services9). This is positioned as an extension of the basic "Federal Food, Drug, and Cosmetic Act" (FD & C Act), supplementing it to realize innovative technological development. Section 3011 promotes the development of "Drug Development Tools (DDT)," which is a process for reviewing the development and improvement of assessment tools, including PROs, to more effectively evaluate the efficacy and safety of drugs in drug development. The FD&C Act also includes an additional provision that promotes the development of DDTs. Section 507 of the FD&C Act additionally defines DDTs as "biomarkers, COAs, and other measures and materials," based on the FDA's Centers for Drug Evaluation and Research ("CDER") and Center for Biologics Evaluation and Research ("CBER"), and defines DDTs as "new drug products, new biological products, and investigational new drug products. and the use of DDTs in new drug development and review processes, such as the application for approval of new drugs, new biological products, and investigational new ^drugs10).

The article also outlines the process by which the FDA will review and certify the scientific validity and eligibility of DDTs developed or improved by drug developers and submitted to the FDA, and provides guidance for companies planning to submit applications, including the "Qualification Process for Drug Development Tools. Tools" was published by the FDA in ^202010). It states that as research advances toward understanding diseases and conditions, the development of qualified DDTs will allow for the approach and integration of new areas in the development of innovative medical technologies and drugs, such as the use of newly developed qualified DDTs to ensure that patients with specific characteristics are abundantly included in the study population. For example, newly developed qualifying DDTs could reduce the size of the study population and shorten the study period by including more patients with specific characteristics in the study population.

At the same time, in 2020, the FDA released the final version of Patient-Focused Drug Development:Collecting Comprehensive and Representative ^Input11). This is the first part of a four-part series of guidance for pharmaceutical companies, FDA staff, and other stakeholders to promote patient-centered drug development, first developed following the release of a draft in 2018. The guidance is designed to incorporate patient experiences and perspectives into drug development and regulatory decisions, and focuses on how to gather comprehensive and representative input from patients and caregivers. Later in the series, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients (guidance for collecting information on symptoms, disease effects, treatment burden, risks and benefits, etc. that patients and caregivers consider important). Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments" (Guidance for Gathering Information on Symptoms, Impact of Disease, Burden of Therapy, and Risks and Benefits that Patients and Caregivers Consider Important, 2022, final version). ¹²⁾ and "Patient-Focused Drug Development. (Guidance on Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, 2022, draft), ¹³ Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making" (Guidance on Methods, Criteria, and Techniques for Incorporating COAs as Endpoints for Use in Regulatory Decision-Making, 2023, draft). ¹⁴ The COA COMPANY

The COA COMPENDIUM, the subject of this analysis, centralizes and summarizes information on COAs used for various diseases and conditions, including PROs, to support understanding of this guidance. It is intended to facilitate communication between authorities, drug developers, and researchers by providing drug developers and others with clear COA information. The FDA recommends that drug developers and researchers use this document as a starting point when considering the incorporation of COA into clinical trials. It should be noted, however, that the COA COMPENDIUM is not a comprehensive list, and the disclaimer that not all COAs listed imply FDA approval and do not provide guidance, and is intended only as a review document. Drug developers are strongly encouraged to review the latest version of disease-specific guidelines when implementing COAs in clinical trials and to discuss COA selection in person with the relevant regulatory review department, regardless of disease or indication.

The information contained in the COA COMPENDIUM, in a pilot version published in January 2016, provides the following information on COAs: (1) if a New Drug Application ("NDA") or Biologics License Application ("BLA") was submitted between 2003 and 2014; and (2) if a COA was submitted between 2003 and 2014 for a new drug application ("NDA") or biologic product ("BLA"). The pilot version, released in January, will include (1) information documents such as the package inserts of New Molecular Entity (NME) drugs that were reviewed and approved in a New Drug Application (NDA) or Biologics License Application (BLA) between 2003 and 2014, (2) COAs that were qualified by CDER's COA Eligibility Assessment ^Program15), (3) COAs that were under review in CDER's COA Eligibility Information collected from COAs that were under review by CDER's COA Eligibility Assessment Program, and in the first revision in 2019, (4) information documents for NMEs reviewed and approved by NDA or BLA from 2003 through June 2017, (5) new indications approved from January through June 2017 or indications related to new indications or new patients for which a supplement, and (6) information on COAs newly qualified through CDER's COA Eligibility Assessment Program. In addition, the second revision in 2021 added (7) information documents for NMEs reviewed and approved by the NDA or BLA from July 2017 through June 2019, (8) supplemental efficacy information related to new indications approved from July 2017 through June 2018, and (9) information on newly qualified COAs.

For NME approvals and efficacy supplements, FDA is reviewing medical opinions for COAs related to clinical studies in the Appendix, cases where the outcome assessment is too complex to be explained in tabular form, cases where there is no reference to guidance that addresses the additional information, and newer FDA-issued guidance that is currently available, The rule states that cases in which the use of a newer or more appropriate COA is recommended in currently available FDA-issued guidance are excluded from the "COA COMPENDIUM," but the results were almost without exception described in the book. Figure 3 briefly shows the relationship between DDT(s) and COA(s). The four COA types covered in COA COMPENDIUM are PRO, ObsRO, Clin-RO, and PerfO, the details of which are described below.

2. Explanation of Data and Methodology

The COA Compendium is organized by disease group under the jurisdiction of the CDER's Drug Review Division. The drug review departments are classified into "Offices" and their subordinate "Divisions," and Table ¹¹⁶⁾ lists the review departments within CDER and the diseases under their jurisdiction. The COA information in the COA COMPENDIUM is derived from clinical trial information for drugs reviewed by the divisions indicated in gray.

The components of the COA COMPENDIUM are listed in Table 2. The explanation is as shown in the table, but an understanding of the terms "COA Context of Use" and "Concept" is particularly important. The COA Context of Use is the intended use of the study drug for the disease for which the COA scale is being used in the clinical trial and the patient categories to be included in the trial. For example, a clinical trial of a drug for acne vulgaris might include "Patients 9 years of age and older with inflammatory lesions of non-nodular moderate-to-severe acne vulgaris (moderate-to-severe Patients 9 years of age and older with inflammatory lesions of non-nodular moderate-to-severe acne vulgaris " ⁸⁾ and in a clinical trial of multiple myeloma, "Prevention of skeletal related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. metastases from solid tumors ^. 8) "Context of Use" is often abbreviated as "COU.

Briefly, the "Concept" describes what is being measured in the patient using the COA as the endpoint of the therapeutic evaluation. Specifically, as shown in Table 2, an individual's clinical, biological, physical, and functional status, experience, and other factors are ^measured10). For example, the Concept from a clinical trial for a specific multiple sclerosis is evaluated in PRO as "Fatigue-related symptoms and associated impacts on daily activities. " ⁸⁾ In some clinical trials for paroxysmal nocturnal hemoglobinuria, the PRO measures the degree of "Disease-related fatigue" and the clinician evaluates the degree of "Transfusion avoidance" as a ^ClinRO8).

Many also evaluate multiple "Concepts" and perform a composite evaluation of them. Composite evaluations sometimes combine different COAs (e.g., ClinRO and PRO), and in some cases combine Biomarker and COA. In the COA COMPENDIUM, Biomarker is only listed when it is a combined evaluation.

As for "COA Types," PRO is as described above; Observer-reported outcome (ObsRO) is a measure related to the patient's health status by a person other than the patient or health care professional, primarily the patient's family or caregiver; ClinRO (Clinician-reported outcome) is a measure related to the patient's health status by a person other than the patient or health care professional, primarily the patient's family or caregiver. Clinician-reported outcome (ClinRO) is a measure based on reports from trained health professionals who observe a patient's health status. PerfO (Performance outcome) is a measure based on standardized tasks that patients actively perform following a set of instructions. And the "COA Tool" is a scale and assessment tool used to measure these ^COAs8), ¹⁰⁾.

The tabulation items (①) and tabulation rules (② to ⑤) for the quantitative analysis of the "COA COMPENDIUM" information in this paper are shown below.

The tabulation items (1) are: i) COAs certified by CDER's COA Eligibility Assessment Program, ii) number of diseases/symptoms, iii) number of study drugs, iv) number of Context of Use by age group (adult, adolescent, child, infant), v) number of Concepts measured for each study drug, vi) number of Composite (vi) Number of evaluations, (vii) Number of COAs for each disease/symptom, and (viii) Number of PROs using Diary (Diary). (ii) "ⅲ) Number of study drugs" was counted for each Context of Use by disease/symptom. (iii) If "ⅳ) Age of Context of Use" was not readable from the table, it was judged from the characteristics of the disease and all were counted as adults. In the case where multiple Concepts were listed as "e.g.," they were counted as 1. (vii) "Number of COAs per disease/symptom" was counted as 1 when a single COA was used in a composite evaluation of multiple Concepts (e.g., ClinRO only). If multiple COAs were used in the composite evaluation, each was counted as 1 (e.g., composite of PRO and PerfO was counted as 1 each).

Results

First, COAs that have been qualified under CDER's COA Eligibility Assessment Program will be listed. Second, we will list the various aggregate results related to COAs that are listed in the COA COMPENDIUM but have not been certified for eligibility.

(1) Qualified COA

Table 3 lists "i) COAs certified by CDER's COA Eligibility Assessment Program. " ⁸⁾, ¹⁷⁾ Seven eligibility-certified COAs are listed, all of which were PROs. The PRO scales assessed subjective symptoms of chronic heart failure, irritable bowel syndrome (constipation type), asthma, COPD, acute exacerbations during bacterial infection in COPD patients, major depressive disorder, and non-small cell lung cancer; only the PRO for asthma (ANSD) was available for use in adolescent patients, and the rest were PRO scales for adults. For details on these scales, please see citation 17.

(2) Quantitative analysis for unqualified COAs

The COA information in the COA COMPENDIUM was quantitatively analyzed as a reference for applicants, although eligibility was not certified. The number of diseases/symptoms was 173, the number of study drugs was 296, and the age range of Context of Use was 227 for adults, 16 for adolescents to adults, 43 for children to adults, 8 for children to adolescents, and 5 for children only. Adolescents were defined as 12 to 18 years of age, and children were defined as 11 years of age or younger, including neonates and infants in some cases.

The total number of "Concepts measured for each drug" was 633. The number of "Ⅵ) Composite evaluations," in which multiple Concepts were evaluated as a composite, was 81, and the number of "Ⅶ) COAs per disease/symptom" was 251 for ClinRO, 216 for PRO, 33 for PerfO, and 15 for ObsRO. The "ⅷ) Number of PROs using Diary" was 74.

Tables 4 and 5 show the details by Office and Division. The disease areas with more than 5 drugs tested and more than 50% of the number of PRO assessments to the number of drugs were "Dermatology and Dentistry Division," "Gastroenterology Division," "Respiratory Medicine, Allergy and Intensive Care Division," "Rheumatology and Transplant Medicine Division," "Neurology Division I and II," "Anesthesiology, Addiction Medicine, Pain PerfO was "Cardiology and Nephrology" 7, "Neurology I & II" 8, "Psychiatry" 3, "Rare Diseases and Medical Genetics" 10, and "Ophthalmology" 4. Allergy and Intensive Care," "Antiviral," "Psychiatry," and "Antitumor" were each 1.

(3) Usage of PROs by disease

The number of PROs used by disease was tabulated according to the CDER review departments, and the Concept (subject of measurement) and Tool (scale) used to measure the PROs listed in the "COA COMPENDIUM" were organized. PRO Concepts were 2 each for "stable angina," "myelofibrosis," and "paroxysmal nocturnal hemoglobinuria," and 1 each for the other PROs. The only disease-specific scales and tools used were cardiomyopathy, neurogenic orthostatic hypotension, hemophilia A, and myelofibrosis.

The "Office of Immunology and Inflammation (OII)" (Table 7) described many clinical trials and test drugs for PRO use. Disease-specific measures were frequently used in skin diseases (skin aesthetics, psoriasis vulgaris), chronic respiratory diseases (bronchial asthma, COPD, cystic fibrosis), rheumatic diseases and analogous diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis). In contrast, generic PRO scales such as Diary and Numerical Rating Scale (NRS) were mainly used in clinical trials of various types of voiding dysfunction, whether idiopathic or drug-induced, and chemotherapy-induced nausea and vomiting.

There were three diseases/symptoms for which the "Office of Infectious Diseases (OID)" (Table 8) used PROs: cystic fibrosis, traveler's diarrhea, and influenza. Pediatric trials for influenza allowed observer evaluation (ObsRO).

The Neurological Office (ON) (Table 9) described the use of PRO scales more frequently for diseases/symptoms in the "Neurology Section. "9 While disease-specific scales were used, rare diseases such as Huntington's chorea and Lambert-Eaton myasthenia syndrome PROs were generic scales such as global impression. PROs for various "epilepsy" symptoms, including genetic disorders, were all diaries, and for pediatric patients, diaries with ObsRO were also possible. In the "Psychiatry" section, all PRO trials were related to sleep disorders, and Diary and General Impression were used. In the Department of Anesthesiology, Addiction Medicine, and Pain Medicine, the only PROs for analgesic trials were generic pain ratings using the Numerical Pain Rating Scale (NPRS) or Visual Analogue Scale (VAS).

The Bureau of Oncology Diseases (OOD) (Table 10) had 4 trials using PROs for pain symptoms in "metastatic castration-resistant prostate cancer," respiratory symptoms in "metastatic non-small cell lung cancer," epileptic partial seizures associated with "tuberous sclerosis," and discomfort symptoms due to "chronic GVHD."

In the "Office of Rare Diseases, Pediatrics, Urology and Reproductive Medicine (ORPURM)" (Table 11), PRO use was listed only in the "Urology, Obstetrics and Gynecology Division". The use of disease-specific scales was allowed for dysuria and sexual dysfunction, but Diary was the main instrument for contraceptive efficacy and female-specific diseases/symptoms such as age-related vasomotor nerve symptoms and genital atrophy.

The "Office of Specialty Medicine (OSM)" (Table 12) PROs were listed only in the "Ophthalmology Section," with dry eye being a disease-specific measure and the others being NRS or VAS for scratchiness, postoperative pain and discomfort symptoms, etc.

Summary and Discussion

This paper investigates the actual use of each COA, especially PROs, in each disease area, as described in the "COACOMPENDIUM" published by the U.S. FDA in 2021. In addition, we analyzed the relationships among clinical trials, investigational drugs, and various data on COAs and PROs used, and discussed several issues.

(1) Update status of described data

As mentioned above, a pilot version of the COA COMPENDIUM was published in 2016, followed by the first edition in 2019 and the second edition in 2021, but there have been no updates since then. However, it is a document published by the review authorities in the United States, the largest drug development country in the world, and there is no other document that organizes COAs used in clinical trials by disease and drug in a centralized manner. Therefore, we believe it is a valuable reference material for implementing PROs in clinical trials. Continuous updating of the COA Compendium is desirable, and the creation of a document that unifies the use of PROs in clinical trials is also desirable in Japan, which intends to promote PPI/E in the future.

(2) Comprehensiveness of data

The COA COMPENDIUM consists of information on NME attachments and other documents reviewed and approved under NDA or BLA from 2003 to 2014 for the pilot edition, 2003 to 2017 for the first edition, and 2017 to 2019 for the second edition, as well as information on new information resulting from indication expansion and COAs approved for eligibility. However, it is not clear that the COA information for NMEs and other NMEs as indicated in the aforementioned definitions is comprehensive for the various clinical trial information collected over a long period of time. Although the list is not intended to be comprehensive, it may contain biased information, and further investigation and research are expected.

(3) Number of qualifying COAs

Although the 21st Century Cures Act was enacted in 2016 and DDT development was expected to be promoted in the U.S. thereafter, the COAs scientifically certified by CDER's COA Eligibility Assessment Program described in the COA COMPENDIUM were limited to seven diseases/symptoms for seven diseases/symptoms, and a look beyond 2021 shows only a new eligibility ^{certification18)} for a special PRO to assess alcohol intake in alcohol-dependent patients. A search of the FDA ^website19) for COA eligibility applications to date shows that there are currently 88. Most of them are still at the Letter of Intent level, which is the entry point for application, indicating the difficulty of developing scientifically valid COAs. At the same time, many of them were only accepted by the FDA when they submitted a Qualification Plan submission, which is a step after the Letter of Intent is accepted, suggesting that there are difficulties in the qualification process as well. As for expectations for the future, all COAs that have been qualified are currently PROs, and "Patient-Focused Drug Development" is thought to be the basic orientation for COA development and CDER qualification. In the future, the development of drugs with new mechanisms of action, new molecular targets, and new modalities to address unmet medical needs is expected to advance further, but from the perspective of co-creation, it will be desirable to develop PROs that will deepen the new and diverse value that patients experience from these new drugs with scientific validity. In this regard, it is desirable to develop PROs that will cultivate new and diverse values experienced by patients through these new drugs with scientific validity.

(4) Usage status of each COA

The COA COMPENDIUM describes the use of 298 study drugs in clinical trials for 173 diseases/symptoms. The total number of patients by age group was 226 for adults only, 16 for adolescents to adults, 45 for children to adults, 6 for children to adolescents, and 5 for infants to children. The total number of COAs by COA was 251 for ClinRO, 216 for PRO, 32 for PerfO, and 15 for ObsRO, indicating that the evaluation of drug efficacy In terms of the number of opportunities, PROs were introduced to the same extent as ClinROs. In contrast, PerfO and ObsRO were less common, especially ObsRO was used for common pediatric and adult conditions such as epilepsy (frequency), asthma symptoms, and influenza symptoms (Tables 7, 8, and 9), allowing selection of PRO and ObsRO for pediatric patients and others who have difficulty accurately expressing self-assessment. The study also included ADHD in adolescents 13-17 years of age. In addition, clinical trials for ADHD in adolescents aged 13-17 years did not describe a PRO, but used the ClinRO and the ObsRO (Connor's Parent Rating Scale).

Based on these analyses, the following issues were considered in the current COA development. (1) The development of COAs, including PROs focused on young people, is not sufficient, (2) ObsRO is limited to diseases common to both children and adults, and its number is small, (3) ObsRO is not described for organic mental disorders such as dementia and neurodegenerative disorders such as Parkinson's disease, and (4) PerfO is not described for organic mental disorders and neurodegenerative disorders. (5) There is no description of ObsRO for rare congenital diseases such as mucopolysaccharidosis and Pompe disease.

It can be inferred that the development of scientifically valid COAs for the above diseases is extremely challenging. However, in order to confront organic mental disorders and neurodegenerative diseases, which are expected to increase due to the rapid aging of the population, and in order to develop innovative drugs to save as many pediatric patients with intractable diseases as possible and reduce the increasing burden on society in the midst of a declining birthrate, we need to develop drugs that are not only evaluated by the patients themselves, but also by caregivers involved in the daily "life" and "life" of patients. In addition to the patient's own evaluation, the viewpoint of caregivers involved in the daily "life" and "life" of the patient will become very important. Especially in discussions on the necessity of evaluating "social value" such as the reduction of caregiving burden by pharmaceuticals, we believe that the advancement of the development of ObsRO and PerfO in addition to PRO is essential and necessary in order to be able to provide a valid explanation of "why and how the burden was reduced".

(5) Status of PRO use by disease area

Of the 173 diseases/symptoms, 82 had some kind of PRO described in the clinical trial. This means that PROs were not used for the remaining 91 diseases/symptoms. While it is true that PRO evaluation is not appropriate for acute conditions directly related to serious events such as acute coronary syndromes and acute stroke, there were only a small number of acute disease trials within the COA COMPENDIUM. In order to expand opportunities for PPI/E in drug development, there may still be room for PRO development in many disease areas.

There was a bias in the diseases/symptoms for which PROs were used, with substantial use of disease-specific PRO scales in autoimmune diseases such as psoriasis vulgaris, rheumatic diseases and allied diseases, and chronic respiratory diseases such as asthma, COPD and cystic fibrosis, cosmetic skin, dysuria and sexual dysfunction. Rheumatic diseases and asthma, in particular, are major diseases that have afflicted many humans since ancient times, although innovative therapeutic agents such as biologics have been developed in recent years, and the abundant development of disease-specific ClinRo and PROs is the result of a long history of clinical research.

Clinical trials for pain symptoms have been dominated by PROs, but unlike earlier, most clinical trials for pain disorders have used basic PRO scales such as NPRS and VAS. The definition of pain by the International Association for the Study of Pain is "an unpleasant sensory and emotional experience associated with or similar to actual or potential tissue damage. " ²⁰⁾ As pain is always a personal experience, as is well known, the essence of pain assessment is subjective, and assessment by PRO is of paramount importance. In light of this, we conducted a simple search on a specialized COA ^website21) to confirm the existence of other pain scales, and found that there are 712 COAs registered on this website that include the word "Pain," and that they are categorized by cause of pain (neuropathic, etc.), condition (chronic, etc.), and underlying disease (dementia, sickle cell, etc.). A variety of pain assessment COAs were developed by pain cause (e.g., neuropathic), condition (e.g., chronic), underlying disease (e.g., dementia, sickle cell disease), organ, site (e.g., back, skin), and age (e.g., pediatric). The majority were PROs, but a few ClinROs and ObsROs also existed. Patients experience pain in a variety of ways. The development of PROs that not only measure changes in pain levels based on numerical values, but also pick up the patient's discomfort expressions in detail for each patient characteristic, is an important element in the promotion of PPI/E and Co-Creation in drug development.

Diaries were frequently used as PROs in clinical trials of voiding dysfunction, sex-related disorders, and epilepsy. diaries provide valuable primary information on the changes in symptoms experienced by patients on a daily basis and appear to be an optimal tool for assessing patient status. Unlike quantitative scales, however, there is concern that the accuracy of information in paper diaries, in particular, may vary depending on the patient's personality, mood, condition, and other factors. Paper-based diaries are not as reliable as the ALCOA (Attributable, Legible, Contemporaneous, and Original), which is an important factor for ensuring data reliability, such as lower reporting time accuracy, lower reporting rule compliance rates, and lower legibility of reported text, ALCOA (Attributable: Attributable, Legible: Legible, Contemporaneous: Concurrent, Original: Original, Accurate: Accurate), which is an important element for ensuring data reliability, has been pointed out as a ^problem7). In recent years, the introduction of "ePRO," an electronic reporting and collection system for diary information, has been recommended as a way to improve this situation ^.22) ePRO is expected to improve data quality and reliability by implementing reporting support functions such as automatic recording of entry time, input reminder function, agile data transfer and feedback, and by ensuring the legibility of text. The company expects that ePRO will improve data quality and reliability. However, even if ePRO is introduced, active cooperation of patients or caregivers in clinical trials, health literacy, and data literacy are essential for co-creation in drug development to take place. In addition, in order to extract maximum value from qualitative primary information obtained from ePRO diaries, the development of AI technology to convert and aggregate unstructured health information expressed by individual patients in a variety of contexts into structured data that is measurable and scientifically valid is an important issue in enhancing the significance of PPI/E and Co-Creation. We believe that this is an important issue in terms of enhancing the significance of PPI/E and Co-Creation.

Finally, there are 8,130 COAs registered on the COA website in citation 21, and a search for COAs containing the word "PRO" yielded 1,580. There are also a plethora of disease/symptom-specific HRQL (health-related quality of life) measures that have been developed," according to Citation 7. In order to select the most appropriate PROs for drug development co-creation from among these many developed PROs, or to develop PROs with even higher scientific validity, it is important to provide opportunities for direct communication with patients and listening to their voices, in cooperation with the government and academia. We believe that this will be an important initiative for the pharmaceutical industry in the future.

Conclusion

Although the COA Compendium did not include many examples of PRO use for oncology, the promotion of Patient-Focused Drug Development is also attracting attention in the field of oncology. The National Cancer Institute (NCI) has developed a PRO scale, PRO-CTCAE (Patient-Reported The Japanese version of the PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events ⁾ was developed by the Japan Clinical Oncology Research Group.) Its Japanese version was approved by the Japan Clinical Oncology Group (JCOG) and published on the NCI website in ^201724).

In 2023, NCI reported a paper on the quantitative analysis of COAs used in clinical trials conducted between 1985 and 2020, divided into oncology and nononcology ^trials25). Of the clinical trials analyzed, 18% of oncology trials and 26% of nononcology trials used some type of COA, of which 84% and 78% used PROs, respectively, pointing out that PROs are used much more frequently among the COA types. As issues, he pointed out that the number of trials using COA in early phase trials was small, and that in cancer clinical trials, 17% of treatment-focused trials used COA, while 49% of supported care trials used COA, but this was still less than half. However, even so, less than half of the patients were treated with COA. We would like to provide opportunities for further research on COAs and PROs, including these issues.

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