Regular Article
Safety Evaluation and Information Provision for Appropriate Drug Usage in Elderly Patients in Japan
2024 Volume 47 Issue 10 Pages 1631-1636
Details
2024 Volume 47 Issue 10 Pages 1631-1636
The elderly Japanese population is growing rapidly due to increasing longevity and declining birth rates. These findings have implications for drug development and safety in elderly patients; however, the Japanese stakeholders have been slow to adapt. This study aimed at examining methods for providing sufficient information on safe use of pharmaceuticals in elderly patients in Japan. For new drugs recently approved in Japan for diseases with a high prevalence among the elderly, we investigated the state of safety information provision for elderly patients through the package insert and also safety data evaluation in elderly patients in clinical studies. Of the 64 targeted drugs, only 14 provided geriatric use information based on clinical study data or indication, 38 had general cautionary descriptions, and 12 did not have geriatric use information. Most drugs met the recommendation of enrolling >100 elderly patients in the clinical development program. However, a discrepancy was observed in the proportion of elderly patients in clinical trials compared to that in real-world clinical setting. Twenty-nine drugs compared the incidence of key adverse events (AEs) in elderly and younger patients, whereas 25 only reported the overall incidence of AEs. To improve healthcare outcomes, healthcare professionals need access to sufficient safety information through package inserts containing data from clinical trials. Marketing authorization holders and regulatory authorities must work together to ensure that such safety information based on sufficient data is included in package inserts.
Aging population is increasing worldwide. The proportion of elderly people aged ≥65 years, which was 10% in 2022, is reported to reach 16% by 2050.1) In Japan, the elderly population is growing rapidly and is expected to exceed 36% by 2045 from the current 29% owing to increasing longevity and declining birth rates.2) This rapidly growing elderly population has important implications for drug development and safety in elderly patients; however, Japanese stakeholders, including regulatory authorities and marketing authorization holders (MAHs) have been slow to adapt.
Nagai et al. analyzed the trends in adverse events (AEs) associated with oxycodone therapy based on the Adverse Drug Reaction Database of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Interstitial pneumonia, drowsiness, and delirium were more frequently reported in elderly patients than in younger patients.3) However, the safety information for elderly patients provided in the package insert of oxycodone hydrochloride is only in general terms, and none of these AEs have been mentioned specifically. Safety information revealed in clinical development programs or post-marketing surveillance is rarely reflected in the package insert, which is a key document for the proper use of medicine.
In the U.S., there is also a growing interest in the proper use of drugs in elderly patients. Budnitz et al. analyzed an AE database and estimated that there were approximately 100000 emergency hospitalizations due to AEs in elderly patients excluding cases of intentional self-harm, drug abuse, treatment failure, or drug withdrawal in the U.S. They reported that the main agents causing AE-related emergency hospitalizations were warfarin, insulins, oral antiplatelet agents, and oral hypoglycemic agents, which accounted for more than 70% of cases.4) A workshop titled “Drug Research and Development for Adults Across the Older Age Span” was held in 2020 by the National Academy of Sciences, Engineering and Medicine, with the aim of examining challenges and opportunities in drug research and development targeting elderly patients.5)
In 1993, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued “Studies in Support of Special Populations: Geriatrics,” a guideline on standard methods for clinical studies to examine the efficacy and safety of medicinal products in the elderly (ICH-E7).6) Despite this guideline, Lau et al. reported that enrollment of the elderly patients in clinical studies for new drugs and biologics were limited and did not represent potential treatment population in the U.S. based on an analysis of 34 products in 7 treatment indications.7) In Japan, Kanda et al. investigated 43 products for seven treatment indications and reported that the proportion of geriatric patients in clinical development programs was smaller than that in a surveyed patient population. Additionally, only a limited number of drugs provided sufficient safety information in their package inserts.8) However, no research has extensively analyzed the number and proportion of drug-exposed elderly patients in clinical studies, and the content of safety information for elderly patients in package inserts in Japan.
This study aimed at examining methods for providing sufficient information on safe use of pharmaceuticals in elderly patients in Japan. We investigated the state of safety information provision for elderly patients through the package insert and also the implementation of safety data evaluations in elderly patients in clinical studies for new drugs to treat diseases and conditions in geriatric populations.
Based on the list of newly approved drugs provided by the PMDA, new active substances (NASs) approved in Japan between April 1, 2012, and March 31, 2023, were selected, excluding vaccines and drugs for prevention and diagnosis. Based on the diseases and conditions listed as “Frequently encountered in drug therapy for the elderly” in the “Guidelines for safe drug therapy in the elderly 2015,”9) 22 diseases with a high prevalence in the elderly were selected. The NASs indicated for these diseases were selected as the research target drugs.
Clinical development strategy of the target drugs was categorized as “multi-regional clinical trial (MRCT)” or “local development” by referring to the review report by the PMDA and summary of new drug application (NDA) document. “MRCT” included drugs with pivotal multi-regional clinical trials in Japan and the U.S. or European countries or bridging strategy. “Local development” represented drugs which were developed and approved with Japanese local clinical trial data.
Safety Information for Elderly Patients on Package InsertsTo investigate the state of safety information provision for elderly patients on the package insert, the contents of subsection “9.8 Geriatric Use” under section “9 Precautions for specific populations” were analyzed. When the package insert was in older format and a subsection did not exist, the entire package insert was reviewed, and the presence and content of any relevant descriptions was analyzed. The content of safety information for elderly patients was classified into the following three categories:
Summaries of NDA document for the initial review of the research target drugs were obtained from the PMDA website. Based on “2.7.4.5.1 Intrinsic factors” in the common technical document (CTD), information on the total number of patients and number of elderly patients (aged ≥65 and 75 years separately) was collected for safety evaluations in patient-targeted studies (mainly, Phase 3 and Phase 2). In cases where the number of elderly patients at “2.7.4.5.1 Intrinsic Factors” were not identified, the necessary information was obtained from “2.7.4.1.2 Overall Extent of Exposure” or “2.7.4.1.3 Demographic and Other Characteristics of Study Population” in the CTD. Based on this information, the proportion of elderly patients to the total number of patients included in the safety evaluation was calculated.
Comparison of the Proportion of Elderly Patients in the Clinical Development Program with That in the Real-World Clinical SettingBased on the report of “Patient survey in 2020” by the Ministry of Health, Labour, and Welfare (MHLW), which comprises data on the populations of patients for individual diseases in total and by 5-year age increments in Japan, the proportion of elderly patients was calculated for each of the 16 diseases targeted in this study.
Analysis and Reporting of AEs in Elderly Patients in Clinical Development ProgramsTo clarify how MAHs had analyzed and reported AE data for elderly patients for each targeted drug, the data presented in the “Age” subsection of the CTD “2.7.4.5.1 Intrinsic factors” was checked, and the description of the incidence of AEs in the elderly and younger patients was classified into the following three categories:
Between the fiscal years (FYs) 2012 and 2022, 457 NASs were approved in Japan. Twenty-three vaccines and eight diagnostic drugs were excluded, and 426 NASs were identified as potential research target drugs. Subsequently, 64 NASs were analyzed in this study based on the 2015 guidelines for safe drug therapy in the elderly. These NASs targeted 16 diseases and conditions that are highly prevalent in the elderly (Table 1). Thirty-three and 31 drugs were approved between the FYs 2012 and 2016, and the FYs 2017 and 2022, respectively. Thirty-three drugs used MRCT strategy, and 31 drugs were approved with local development strategy.
| Treatment indication | Number of drugs included in the analysis N = 64 | Number of drugs with MRCT n = 33 | Number of drugs with local development n = 31 |
|---|---|---|---|
| Insomnia | 2 | 2 | 0 |
| Parkinson’s disease | 6 | 4 | 2 |
| Depression and depressive state | 3 | 2 | 1 |
| Dementia/cognitive impairment | 1 | 0 | 1 |
| Chronic obstructive pulmonary disease | 6 | 6 | 0 |
| Pneumonia | 1 | 0 | 1 |
| Thrombosis | 1 | 1 | 0 |
| Heart failure | 5 | 2 | 3 |
| Hypertension | 2 | 0 | 2 |
| Constipation | 3 | 0 | 3 |
| Diabetes mellitus | 17 | 6 | 11 |
| Hyperlipidemia/dyslipidemia | 2 | 0 | 2 |
| Renal failure/impaired renal function | 1 | 1 | 0 |
| Overactive bladder | 2 | 2 | 0 |
| Osteoporosis | 3 | 1 | 2 |
| Rheumatoid arthritis | 9 | 6 | 3 |
Of the 64 drugs analyzed, only 14 provided specific safety information for elderly patients on their package inserts based on the clinical study data (Table 2). In contrast, 38 had general and standardized cautionary descriptions, such as “generally, physiological functions are reduced for elderly patients, so be cautious about the occurrence of AEs, and administer carefully while closely observing the patient’s progress.” Twelve drugs did not have a “Geriatric Use” subsection or any relevant description on their package inserts. Twelve point one percent (4/33) and 32.3% (10/31) of drugs with MRCT and local development strategy, respectively, reported specific safety information for elderly patients.
| Safety information for geriatric patients on subsection “9.8 Geriatric Use” | Overall number of drugs, (%) N = 64 | Number of drugs with MRCT, (%) n = 33 | Number of drugs with local development, (%) n = 31 |
|---|---|---|---|
| Drug or disease specific safety information provided | 14 (21.9) | 4 (12.1) | 10 (32.3) |
| Only general instruction regardless of results of clinical study provided | 38 (59.4) | 22 (66.7) | 16 (51.6) |
| Subsection “9.8 Geriatric Use” itself omitted | 12 (18.8) | 7 (21.2) | 5 (16.1) |
Abbreviations: MRCT, multi-regional clinical trial.
Sixty-one of the 64 drugs enrolled >100 elderly patients aged ≥65 years in Phase 2 and Phase 3 studies, adhering to the ICH-E7 recommendations. Three drugs, vortioxetine hydrobromide, elobixibat hydrate, and lurasidone hydrochloride for depression, chronic constipation, and schizophrenia, respectively, enrolled <100 elderly patients for safety evaluations. Information on the number of patients aged ≥75 years included in the safety evaluation population was available for only 26 drugs.
Comparison of the Proportion of Elderly Patients in the Clinical Development Program with That in the Real-World Clinical SettingThe proportion of elderly patients aged ≥65 years to the total patient population in the real-world clinical setting and that in the clinical development program for each research target drug by disease was plotted (Fig. 1a). The proportion of elderly patients in clinical studies was underrepresented compared to that in real-world clinical settings for 15 diseases, except for dementia, where the proportion of elderly patients aged ≥65 years on donepezil hydrochloride was 97.9%, which was very close to the actual proportion of elderly patients (98.2%). Only 5 drugs for dementia, heart failure, and osteoporosis exceeded the proportion of 60%, all of which were approved between the FYs 2017 and 2022.
Vertical axis depicts the proportion of elderly patients aged ≥65 years (Fig. 1a) and ≥75 years (Fig. 1b). Cross indicates the proportion of elderly patients in the actual patient population for the disease based on the “Patient survey in 2020.” Each white triangle and black circle represent the proportion of elderly patients in the clinical development program of drugs which were approved between fiscal years 2012 and 2016, and between fiscal years 2017 and 2022 in Japan, respectively. For overactive bladder, the number of patients by age was not aggregated in the “Patient Survey in 2020.” Data on the number of elderly patients aged ≥65 years was not available for opicapone (for Parkinson’s disease) and sodium ibandronate hydrate (for osteoporosis) in the common technical document, and they were excluded from Fig. 1a.
The same analysis was conducted for population aged ≥75 years (Fig. 1b). Only 26 drugs in 12 indications had these patients in the clinical development programs. Discrepancies in the proportion of elderly patients aged ≥75 years between the clinical development programs and the real-world clinical setting for 8 diseases were greater than those observed when targeting population aged ≥65 years. Twelve drugs were approved between the FYs 2012 and 2016, and 14 drugs were approved between the FYs 2017 and 2022. There were only 4 drugs of which the proportion of elderly patients aged ≥75 years in the clinical development programs exceeded 30%, and 3 out of the 4 drugs were approved between the FYs 2017 and 2022.
Analysis and Reporting of AEs in Elderly Patients in Clinical Development ProgramsOf the 64 drugs analyzed, 29 drugs reported the incidence of AEs in both elderly and younger patients, with quantitative comparisons. For 25 drugs, the incidence of AEs between elderly and younger patients was analyzed; however, only the overall incidence of AEs was reported. A quantitative analysis of the incidence of AEs in elderly patients was not performed for the remaining 10 drugs, thereby limiting the means of obtaining safety information for the geriatric population (Table 3). The percentage of drugs for which the incidence of AEs in elderly patients was not quantitatively compared to that in younger patients was 6.5% (2/31) for local development strategy and 24.2% (8/33) for MRCT strategy.
| Comparison of AEs between the elderly and younger patients | Overall number of drugs, (%) N = 64 | Number of drugs with MRCT, (%) n = 33 | Number of drugs with local development, (%) n = 31 |
|---|---|---|---|
| Comparison of the overall and individual incidence of AEs (frequent or noteworthy AEs in the elderly) between elderly and younger patients. | 29 (45.3) | 16 (48.5) | 13 (41.9) |
| Comparison of only the overall incidence of AEs between elderly and younger patients. | 25 (39.1) | 9 (27.3) | 16 (51.6) |
| No quantitative comparison of AEs by age performed. | 10 (15.6) | 8 (24.2) | 2 (6.5) |
Abbreviations: AE, adverse event; MRCT, multi-regional clinical trial.
This study aimed at examining methods for providing sufficient information on safe use of pharmaceuticals in elderly patients in Japan. Because we studied NASs to treat diseases or conditions that are frequently encountered in Japanese elderly patients, we expected that the package insert described adequate safety information to elderly patients based on data from the clinical trials. However, it was not always sufficient; twelve (18.8%) of the 64 investigated drugs omitted subsection associated with “Geriatric Use” on their package inserts, although almost all the drugs had obtained safety data from >100 elderly patients in their clinical development programs. The MHLW has announced that generalized safety information, such as “generally, physiological functions can decrease for elderly patients; therefore, care should be taken when the drug is administered to elderly patients,” is not needed to be included in subsection “Geriatric Use” on the package insert if safety profile for elderly patients has been confirmed through clinical studies.10) However, this does not imply that this subsection can be omitted. MAHs are responsible for providing proper information to assess the safety risks associated with drugs to their users, such as prescribing physicians, through package inserts. The guidelines for preparing package inserts should be improved so that MAHs can provide appropriate safety information for elderly patients based on data from clinical trials, rather than simply omitting subsection “Geriatric Use.”
Thirty-eight drugs (59.4%) provided only generalized safety information on their package inserts. The information typically read: “Generally, elderly patients have reduced physiological functions, so be cautious of AEs and administer carefully while closely observing the patient’s condition.” These descriptions do not provide any specific safety information associated with the drug or target disease. One reason for including such descriptions may be to avoid causing excessive concern for healthcare professionals, which could lead to prescription avoidance. However, there is a risk that most drugs with uniform safety information will not fulfill the original purpose of the package insert.
In the U.S., a draft Guidance for Industry, “Geriatric Information in Human Prescription Drug and Biological Product Labeling” was issued in 2020.11) The guideline recommends that for drugs that will be used by both elderly and younger patients, information on the presence or absence of differences in the safety profile between elderly and younger patients should be provided based on clinical trial results in any of three different scenarios (Table 4, Scenario 1–3); moreover, it should be clearly stated if the evaluation of differences in the safety profile between elderly and younger patients was insufficient. Clarifying the presence or absence of differences in the safety profiles of elderly and younger patients in the Japanese package inserts will also contribute to the proper use of drugs for elderly patients. If it is impossible to compare the safety profile between elderly and younger patients owing to an insufficient number of evaluated patients or other reasons, it should be stated explicitly so that prescribers can consider this when determining appropriate usage.
| Scenario | |
|---|---|
| 1.1 | When information is sufficient to detect differences in safety and/or effectiveness between elderly and younger adult patients AND no observed differences in safety and/or effectiveness for elderly patients compared to younger adult patients. |
| 1.2 | When information is sufficient to detect differences in safety and/or effectiveness between elderly and younger adult patients AND differences in safety and/or effectiveness for elderly patients compared to younger adult patients. |
| 1.3 | When information is insufficient to detect differences in safety and/or effectiveness between elderly and younger adult patients. |
Only 14 (21.9%) of the 64 drugs analyzed had safety information for elderly patients on the package insert based on the characteristics of the target indication or safety data obtained from the clinical development program. For drugs used to treat rheumatoid arthritis, specific information about the incremental incidence of serious AEs, such as severe infections, in elderly patients compared to younger patients in the clinical development program was provided. Sodium-glucose co-transporter-2 (SGLT2) inhibitors approved for diabetes cited safety information on their package inserts based on the mechanism of action that “dehydration symptoms may be less likely to be recognized in elderly patients.” Additionally, some of the drugs included safety information based on clinical trial results that the incidence of certain AEs increased in patients aged ≥75 years compared to those <75 years. Safety information based on data obtained during clinical development is specific and practical and is beneficial for ensuring the safety of elderly patients. It is necessary to describe concrete safety information on package inserts based on data to ensure the appropriate use of drugs. Drugs developed through local development strategy had a numerically higher percentage of providing specific safety information for elderly patients compared to those developed through MRCT strategy (32.3 vs. 12.1%); however, the drugs with local development strategy included 11 diabetes drugs, among which 5 were SGLT2 inhibitors that provided relatively comprehensive information for the elderly patients in their package inserts. Therefore, it was difficult to fully discuss the relationship between the adequacy of information provided for elderly patients and the development strategy employed.
Most of the 64 drugs analyzed met the recommendations of the ICH-E7 guidelines to include over 100 elderly patients in their development programs to evaluate safety and efficacy with new drugs. However, a discrepancy was revealed in the proportion of elderly patients in clinical development programs compared to the real-world clinical setting. The ICH-E7 guidelines and Questions & Answers recommend that pharmaceutical companies enroll a sufficient number of elderly patients in confirmatory and long-term safety studies to adequately represent elderly patients in the real-world clinical setting.12) However, most of the investigated drugs did not enroll sufficient number of elderly patients into the clinical trials to mimic ration of elderly patients in the real-world clinical setting. This trend did not seem to have changed throughout the study period. The guidelines also require investigation of the differences in efficacy and safety profiles between elderly and younger patients.12) We recognize that elderly patients may be less willing to participate in clinical trials, and that clinical investigators may be hesitant to enroll them because of concerns about age, concomitant medications, and the ability to participate in long-term clinical studies. However, the enrollment of >100 elderly patients aged ≥65 years was not always sufficient to compare safety profile between elderly patients and younger patients. Manufacturers should strive to enroll elderly patients to their clinical studies in proportions that reflect the distribution of the elderly patient population in the real-world clinical setting. Furthermore, it is essential to evaluate the safety profile of elderly patients in comparison with that of younger patients.
The number of drugs that represented stratified analysis results of safety evaluations for elderly patients aged ≥75 years in the NDA document was limited, and did not meet the recommendations of the ICH-E7. Safety evaluations of drugs for patients aged ≥75 years, who account for >15% of the entire Japanese population,2) are not being adequately implemented in clinical development programs. Maanen et al. highlighted similar issues and advocated for a revision of the ICH-E7 to enhance data collection for patients aged ≥75 years.13) Analyzing safety data in clinical development programs would be beneficial not only for elderly patients aged ≥65, but also for those aged ≥75 or even ≥85 years. This analysis would provide relevant safety information through the package insert. A discussion on revising the ICH-E7 guidelines, issued in 1993, would be meaningful in order to adapt them to the changing demographics of the contemporary world.
The appropriate use of prescription drugs for elderly patients is of paramount importance in Japan, where the proportion of elderly people in the population is projected to exceed 36% by 2045.2) Furthermore, mortality rates related to adverse drug events have seen a global increase in elderly patients, including Japan.14,15) Therefore, it has become crucial to communicate drug safety information for elderly patients to prescribers and healthcare professionals through package inserts that include data from clinical trials. This communication is vital for the appropriate use of drugs in elderly patients. Compliance with the ICH-E7 guidelines is essential to ensure safer drug use in elderly patients. Stakeholders should consider practical and effective methods to evaluate drug safety in elderly patients during the clinical development phase, and on how to disclose their evaluation results through package inserts and NDA documents. Those actions improve quality of safety communication among stakeholders and ensure the appropriate use of drug in elderly patients.
This study has some limitations. First, we targeted diseases and conditions with a high prevalence in the elderly, but other diseases occur frequently in geriatric populations, such as species, cataracts, bronchiectasis, interstitial pneumonia, and malignant neoplasms. Second, of the 64 drugs investigated, 17 (26.6%) were for diabetes and nine (14.1%) for rheumatoid arthritis. This distribution may have introduced bias into this study.
More than three-quarters of the research target drugs did not provide sufficient safety information for elderly patients in their package inserts. Furthermore, the representation of elderly patients in clinical development programs was disproportionately low compared to their presence in real-world clinical settings. To improve healthcare outcomes for elderly patients within the constraints of available resources, healthcare professionals should be provided with sufficient safety information through package inserts that include data from clinical trials. MAHs bear the responsibility of communicating safety information clearly, enabling prescribers to make informed decisions about the risks associated with the use of drugs in elderly patients. The regulatory authorities should revise the guidelines pertaining to the information required in package inserts and ensure the inclusion of such vital information.
The authors declare no conflict of interest. MO is a full-time employee of Chugai Pharmaceutical Co., Ltd. The views expressed herein are the result of independent work and do not represent the view and finding of Chugai Pharmaceutical Co., Ltd.
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