Representation of older patients in clinical trials for drug approval in Japan

Abstract

To examine how target patients seen in clinical practice are represented in clinical trials for approved drugs in Japan, we compared the age distribution of older patients enrolled in confirmatory clinical trials for regulatory approval with that of the estimated actual patient population. Drugs for 6 chronic conditions common among older patients (diabetes mellitus, hypertension, rheumatoid arthritis, non-small cell lung cancer, depression and Alzheimer's disease) launched by 2012 in Japan were selected. The disparity in age distribution between patients in trials and patients seen in clinical practice varied depending on the disease, but older patients, especially those aged 75 or older, were generally underrepresented in clinical trials for regulatory approval in Japan. Under-representation of older patients in hypertension trials was particularly marked compared to other conditions, despite the similarity in age distribution of patients seen in clinical practice. One factor causing this disparity may be an upper age limit in clinical trial protocols. More effort is needed to properly characterize the benefits and risks of drugs for older patients. This should include the active enrollment of older patients in clinical trials, the establishment of better assessment tools such as pharmacometric approaches, and the appropriate planning and conducting of post-marketing surveys and studies.

Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A post‐marketing study (J‐STEP/EL Study)

“…Elderly male and female patients aged ≥65 years with type 2 diabetes mellitus without exclusions for concomitant diseases and concomitant medications were enrolled. In contrast in the preapproval clinical trials, a number of elderly patients were excluded because of the number and/or severity of their comorbidities, which were defined in the exclusion criteria, resulting in limited safety information for elderly patients. Furthermore, elderly patients aged ≥65 years comprise 63.4% of all type 2 diabetes mellitus patients treated in Japan.…”

Comparison of Drug Use Between Clinical Practice and Regulatory Approval: Results in Older Japanese Patients With Rheumatoid Arthritis, Diabetes, High Blood Pressure, or Depression

“…3 One of the factors that lead to a decrease in the number of older patients in clinical trials is the setting of an inclusion or exclusion criterion of clinical trials based on age. 8,15 Our data suggest that deterioration of physiological function such as liver or kidney in older patients is also a major reason why older patients are usually excluded from clinical trials for regulatory submission for drug approval. Conducting clinical trials without an upper age limit has been suggested, 8,15 but it may be challenging to include very old patients because of deterioration of physiological function.…”

“…8,15 Our data suggest that deterioration of physiological function such as liver or kidney in older patients is also a major reason why older patients are usually excluded from clinical trials for regulatory submission for drug approval. Conducting clinical trials without an upper age limit has been suggested, 8,15 but it may be challenging to include very old patients because of deterioration of physiological function. Therefore, we should be aware of certain limitations in enrolling older patients in clinical trials, although all efforts should be made to include older patients in clinical trials as described in ICH E7 Q&A.…”

“…These results support our previous finding showing that patients in clinical practices were older than those in clinical trials and also indicate generalizability of our data to the national population in Japan. 5,8 We found that the dose of drugs prescribed to older patients with depression or rheumatoid arthritis treated in clinical practice was lower than the standard approved dose. The difference became larger as patient's age increased.…”

“…[4][5][6][7] As a result, the age distribution of patients in Japan differs widely between actual clinical practice and participation in clinical trials. 8 Therefore, it is necessary to investigate how the lack of data in older patients in clinical trials affects drug use and safety profile such as adverse drug events (ADEs) in clinical practice in Japan. We conducted a retrospective cohort study by use of electronic medical record (EMR) data and examined differences in drug use such as dose and ADEs between clinical practice and clinical trials performed for regulatory approval.…”