Drug Approval In Japan Research Articles

Characteristics of Clinical Trials for the US Food and Drug Administration Accelerated Approval and Subsequent Confirmatory Trials: Implications for Drug Approval in Japan.

The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.

Characteristics of Asian Participation in Multi-regional Clinical Trials Reviewed for Drug Approval in Japan: Opportunities for Collaboration Between South-East Asia, East Asia, and Japan.

Although the percentage of multi-regional clinical trials (MRCTs) submitted for drug approval in Japan increased significantly since the 2007 publication of the regulatory guideline, "Basic principles on global clinical trials", strategic collaborations between Asian countries will be important to promote MRCTs in accordance with the ICH E17 guideline published in 2017. In this study, characteristics of MRCTs reviewed for drug approval in Japan, especially those with participation by South-East Asia and East Asia, were investigated to explore opportunities for collaborations on global drug development in Asia. More than 90% of reviewed trials were conducted as global MRCTs. In addition to Japan, South-East Asia has participated in various types of MRCTs in terms of total numbers of subjects and countries. However, South-East Asia participation was lower in large-size MRCTs (total sample size ≥ 1000) than in middle- (500 ≤ total sample size < 1000) and small-size MRCTs (total sample size < 500). Furthermore, similar clinical trials for the same indications to the MRCTs without South-East Asia were rarely conducted separately in South-East Asia. Participation of other Asian countries did not affect the percentage of Japanese subjects enrolled in an MRCT, but did significantly increase the percentage of participating Asian subjects. These results suggest that additional opportunities for collaboration on MRCTs may be possible between Japan and other Asian countries, especially more collaborations with South-East Asia in the large-size MRCTs. More data of Asian populations from MRCTs will be useful for exploring an important ethnic factor affecting drug response, and will provide a sound scientific basis in considering the application of the pooled data concept in Asia, as described in the ICH E17 guideline.

Real-world safety and effectiveness of canakinumab in patients with cryopyrin-associated periodic fever syndrome: a long-term observational study in Japan.

A post-marketing all-patient surveillance program was conducted to evaluate the safety and effectiveness of canakinumab, a monoclonal anti-interleukin-1β antibody, in patients in Japan with cryopyrin-associated periodic fever syndrome (CAPS), including familial cold auto-inflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease. All patients with CAPS who received canakinumab treatment after drug approval in Japan were registered in this non-interventional, observational study. The observation period per patient was two years. Patients newly treated with canakinumab (New patients; NP) and those continuously treated with canakinumab following clinical trials (Roll-over patients; RP) were included. Data collection of clinical symptoms affecting physical function and prognosis was not mandated but assessed where available. Here, the interim results are reported. Of 87 patients in the safety set, the proportion of patients with any adverse drug reactions (ADRs) and any serious ADRs was 31.03% and 3.45%, respectively. The most common ADRs reported under system organ class were infections and infestations (20.69%). Of 84 patients in the effectiveness set, 75.76% and 83.33% of NP and RP, respectively, were responders at Week 24, achieving complete response without relapse. Responder rates were maintained up to Week 104. Clinical symptoms affecting physical function and prognosis remained unchanged in over half of those patients. Interim results provided the safety profile of canakinumab in a real-world setting, and identified no new safety concerns. Treatment with canakinumab has suggested sustained remission in the majority of patients in the real-world setting.

Real-world safety and effectiveness of canakinumab in patients with tumour necrosis factor receptor-associated periodic syndrome or hyperimmunoglobulinaemia D syndrome: Interim results from post-marketing surveillance in Japan.

To assess the real-world safety and effectiveness of canakinumab in patients in Japan with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate kinase deficiency/hyperimmunoglobulinaemia D with periodic fever syndrome (MKD/HIDS). All patients with TRAPS or MKD/HIDS who received canakinumab following drug approval in Japan were registered in a post-marketing all-patient surveillance with a 2-year observation period. Herein, the interim results are reported. Fifteen patients with TRAPS and seven with MKD/HIDS were included in the safety and effectiveness analysis set. Adverse drug reactions were reported in 26.67% (n = 4) and 42.86% (n = 3) of TRAPS and MKD/HIDS patients, respectively. Most common adverse drug reactions were upper respiratory tract inflammation (13.33%, n = 2) and pyrexia (42.86%, n = 3) in TRAPS and MKD/HIDS patients, respectively. No serious adverse drug reactions were observed in either TRAPS or MKD/HIDS patients. The proportion of responders was 46.67% and 14.29% in the TRAPS and MKD/HIDS groups, respectively; 72.73% and 66.67% achieved clinical remission, while 90.91% and 66.67% achieved serological remission by Week 4 in the TRAPS and MKD/HIDS groups, respectively. These interim results provide the first evidence of the real-world effectiveness of canakinumab in patients with TRAPS or MKD/HIDS in Japan. No new safety concerns were identified.

Lag Time for New Innovative, First-in-Class, Drug Approval in Japan

Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee's request. First-in-class drugs were developed at the Committee's request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

Regulatory issues and the potential use of Bayesian approaches for early drug approval systems in Japan.

Bayesian methods quantify and interpret the therapeutic effects of investigational drugs based on probability statements of the posterior distribution. However, the basic principle underlying the use of Bayesian methods in registration trials for new drug applications in Japan has not been adequately discussed. Motivated by the two drug approval systems for early approval recently enacted in Japan, we present our perspectives on the application of the Bayesian approach in registration trials in Japan. These are based on discussions among academic, industry, and regulatory experts at invited workshops. Based on the aforementioned early approval systems, we discuss putative common regulatory issues related to the use of the Bayesian approach and introduce instances of clinical trials in which the Bayesian approach is expected to be used. This article provides a well-defined premise for the discussion between industry and regulatory agencies on the use of Bayesian approaches for early drug approval in Japan.

Preclinical and clinical researches of Denileukin Diftitox (Genetical Recombination) (Remitoro®), a novel agent for T-cell lymphoma

Denileukin Diftitox (DD) is a recombinant fusion protein of diphtheria toxin (DT) fragments and human interleukin-2 (IL-2). DD binds to IL-2 receptor (IL-2R) expressed on tumor cells and is taken up into the cells. Subsequently, DT fragments with adenosine diphosphate ribosylation enzyme inhibit protein synthesis, then ultimately trigger cell death. DD binds to both high- and intermediate-affinity IL-2Rs via IL-2 domain and inhibits growth of human T-cell lymphomas cell lines. E7777, which contains DD as an active component, has improved purity and an increased percentage of active monomer compared with the approved drug E7272 (ONTAK in the US, not approved in Japan). In the phase I clinical study in Japanese patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), the maximum tolerated dose and recommended dose of E7777 were 9 μg/kg/day (administered on Days 1-5 of each cycle) based on the evaluation of dose-limiting toxicity. In the phase II clinical study, the objective response rate was 36.1%, showing comparable efficacy to existing therapies. E7777 showed anti-tumor activity observed across the range of CD25 expression. Grade 3 or higher adverse events (AE) occurred in 94.6%, and serious AE such as capillary leak syndrome and rhabdomyolysis were reported. Therefore, safety monitoring activities have been continued along with alerting related events. Based on these results, E7777 obtained a new drug approval in Japan in March 2021 for the indication of relapsed or refractory PTCL/CTCL.

Points to Consider for Implementation of the ICH E17 Guideline: Learning from Past Multiregional Clinical Trials in Japan.

We identified the major points that are described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline but have not been considered in the past multiregional clinical trials (MRCTs) used for drug approval in Japan to elucidate potential challenges in the implementation of the ICH E17 guideline in Japan. Based on the analysis of 167 MRCTs of 130 drugs, several points, such as the same dose setting and consistency between the overall and Japanese populations, in addition to good clinical practice compliance, have been well considered in ≥ 75% of MRCTs. In contrast, the use of relevant guidelines for disease and primary end point definitions, standardization of efficacy/safety information, sample size allocation, as well as training/validation on subject selection and primary end point, have been addressed less adequately and may need to be considered when planning future MRCTs. This study provides useful information for the implementation of the ICH E17 guideline in Japan.

Evolving Landscape of New Drug Approval in Japan and Lags from International Birth Dates: Retrospective Regulatory Analysis.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first‐in‐world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008–2011), 1.5 and 2.6 in the second tertile (2012–2015), and reduced to 1.3 and 2.2 in the third tertile (2016–2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one‐fifth of the new drugs approved in Japan are first‐in‐world approvals. Drug lag has been greatly decreased, although it still exists.

Notable Differences in Drug Lag Between Korea and Japan of New Drugs Between 2009 and 2017.

Although great efforts have been made to address delays in new-drug approvals between different regions, little is known regarding drug lag in Korea. We compared drug lag in Korea with that in Japan, which is well known through many previous studies. We extracted approval information from public data obtained from the regulatory authorities on all new drugs that were listed in both Korea and Japan between 2009 and 2017. Relative drug lag represented the difference between the date of approval in the country of interest and the date of the first global approval. Relative drug lag was measured as median approval lag. Multiple regression models were used to identify the factors associated with drug lag. The factors considered included origin of substance, nationality of manufacturer, original approval date, orphan drug status, and therapeutic class. In total, 394 new drugs were approved in both countries between 2009 and 2017. The median approval lag was 28.2 and 54.1 months in Korea and Japan, respectively. Domestic company drugs were associated with longer median approval lag in Korea ([Formula: see text]), sensory organ drugs were associated with shorter median approval lag in Japan ([Formula: see text]), and orphan drug status was associated with longer duration of drug approval in Japan ([Formula: see text]). Notable drug lags were observed in both Korea and Japan, but the lag was shorter in Korea. Inclusion of global clinical trials and existence of prior knowledge in new drug development were critical to reduce drug lag.

Future Perspectives for the Treatment of Diabetes: Importance of a Regulatory Framework.

The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union. Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents. No difference in the total number and types of approved drugs among the 3 regions was found (P = .173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions (P < .001 by analysis of variance repeated measures test adjusted by the Holm method). Currently, 6 drugs with known modes of action are being developed for type 1 diabetes in Japan, whereas at the end of 2016, nearly 7-fold more products with novel modes of action were in clinical development in the United States. Antidiabetic drug development in Japan costs less than that in the other regions, although novel development is less active because of regulatory differences. To achieve better pharmacotherapy for diabetes, the regulatory framework requires careful consideration.

Notable Differences in Drug Lag Between Korea and Japan of New Drugs Between 2009 and 2017

Although great efforts have been made to address delays in new-drug approvals between different regions, little is known regarding drug lag in Korea. We compared drug lag in Korea with that in Japan, which is well known through many previous studies. We extracted approval information from public data obtained from the regulatory authorities on all new drugs that were listed in both Korea and Japan between 2009 and 2017. Relative drug lag represented the difference between the date of approval in the country of interest and the date of the first global approval. Relative drug lag was measured as median approval lag. Multiple regression models were used to identify the factors associated with drug lag. The factors considered included origin of substance, nationality of manufacturer, original approval date, orphan drug status, and therapeutic class. In total, 394 new drugs were approved in both countries between 2009 and 2017. The median approval lag was 28.2 and 54.1 months in Korea and Japan, respectively. Domestic company drugs were associated with longer median approval lag in Korea (β = 12.076, P = .015), sensory organ drugs were associated with shorter median approval lag in Japan (β = -46.144, P = .009), and orphan drug status was associated with longer duration of drug approval in Japan (β = 9.695, P = .024). Notable drug lags were observed in both Korea and Japan, but the lag was shorter in Korea. Inclusion of global clinical trials and existence of prior knowledge in new drug development were critical to reduce drug lag.

Factors Affecting Drug-Development Strategies in Asian Global Clinical Trials for Drug Approval in Japan.

We assessed the current status of Asian global clinical trials (GCTs) and factors, such as therapeutic areas, main metabolic enzymes targeted, approval status in the United States or the European Union, development strategies, influencing drug‐development strategies in Asian GCTs and in general GCTs for drug approval in Japan. The findings suggested that region‐specific diseases in Asia, intrinsic and extrinsic ethnic differences between Japanese/Asian and Caucasian populations, and the status of the drugs’ development in the United States or the European Union all affected Asian GCTs. These factors may influence the drug development process in Asian GCTs. Furthermore, we found that pharmacokinetics data in Asian GCTs comparing similarities between Japanese and other Asian populations were mainly obtained from late‐phase trials, which may delay the identification of potential differences in ethnic factors.

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

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.

Post-Marketing Surveillance of Bortezomib Treatment for Multiple Myeloma (MM) in Japan: Results of Interim Analysis by the Velcade Japan Proper Use Guideline Committee

[Background] Bortezomib (VELCADE® for Injection 3 mg) was approved in Japan on October 10, 2006 for the treatment of relapsed or refractory MM. As required for most oncology drug approvals in Japan, a special post-marketing surveillance program was implemented on December 1, 2006, enrolling all patients treated with bortezomib to assess its safety and efficacy from actual medical practice experience in Japan.[Patients and Methods] This surveillance is a prospective program designed to enroll patients before starting treatment with bortezomib. It included 1048 consecutive patients treated with bortezomib in the first year after the drug approval in Japan. This report summarizes the results of an interim analysis of safety and preliminary efficacy of the first two cycles of bortezomib in 525 patients. Patients are to be observed for 3 years at maximum. Observational items include: gender, age, medical history, prior therapies, administration of bortezomib, concomitant drug/therapy, laboratory testing, physical examination, clinical symptoms, anti-tumor effects, and adverse event (AE) collection. In addition, for AEs of special interest, such as lung disorder/interstitial lung disorder (LD/ILD), cardiac dysfunction, tumor lysis syndrome (TLS), peripheral neuropathy, hematotoxicity, pyrexia, skin disorder, hypotension and gastrointestinal disorder, heightened surveillance was conducted to capture onset, clinical course and outcomes.[Results] Males outnumbered females (55.8% [293/525] vs. 44.2% [232/525]). Patients elder than 50 years old accounted for 92.6% (486/525). Most of the patients were in stage III by both the International Staging System and Durie & Salmon system. More than half of the patients (59.1% [310/525]) had a duration of illness ranged from 1 to 5 years. Coexisting medical conditions were present in 62.3% (327/525) of patients; the most common was hypertension (17.5%). 7.6% and 10.5% of patients had coexisting medical conditions related to lung disease or heart disease, respectively. Most of the patients had received prior treatment for MM, which included MP (melphalan, prednisolone), thalidomide, dexamethasone, VAD (vincristine, doxorubicin, dexamethasone), and stem cell transplantation. The most commonly observed adverse drug reactions (ADRs) were abnormal changes in hematological laboratory tests (74.3%). Incidence of serious ADRs was 21.1% (111/525). The most frequent serious ADRs were low platelet count (5.3% [28/525]) and peripheral neuropathy (2.1% (11/525). LD/ILD was seen in 4.2% (22/525). TLS was observed in 5.0% (26/525). With regard to the preliminary analysis of anti-tumor effect, the overall response rate as determined by the investigator-based clinical evaluations was 50.2% (257/512). The overall response rate based on M-protein concentration was 41.8% (214/512). 12 (2.3%) patients died within 30 days after the final administration of bortezomib. Progression of disease was the most common cause of death, and worse performance status prior to initiating bortezomib was associated with early mortality.[Conclusion] Based on the interim analysis, this post-marketing surveillance reveals no new safety signals in Japanese patients with relapsed/refractory MM treated with bortezomib. The incidence rates of AEs of special interest were comparable to those observed outside Japan except for LD/ILD which was less than those initially reported for the Japanese population.

Clinical trials for drug approval: a pilot study of the view of doctors at Tokushima University Hospital

The development of new and useful pharmaceutical drugs is essential in order to improve the quality of drug therapeutics. Clinical trials play a central role in drug development. Over time, the clinical trial infrastructure has improved and is now integrating the contribution of clinical research coordinators (CRC). Nevertheless, the attitude of doctors towards clinical trials still favors conventional/historical methodologies. In the present study, we explored the view of doctors towards clinical trials for drug development, in order to improve communication among participants, sponsors, and investigators.A questionnaire was designed for this pilot study. The questionnaire included general attitudes, difficult points, the benefit of doctors in participating as investigators, special attention requirements, and the expected role of CRC in clinical trials for drug approval. In addition, the appropriate use of the outpatient clinic was examined. The questionnaire was provided to doctors in each department of Tokushima University Hospital in 2000 and 2004. Because of the small number of subjects included in this pilot study, no statistical analysis is presented. A total of 89 (81%) and 62 (56%) doctors among 110 responded to the survey in 2000 and 2004, respectively. Inquiries about the familiarity of the physicians with clinical trials for drug approval revealed that 84% in 2000 and 66% in 2004 were aware of such trials. The attitude towards participating as investigators in the clinical trials was favorable, with a response of 66% in 2000 and 58% in 2004. Patients' refusal and the informed consent process were considered difficult areas by many doctors. Expected roles of CRC included activities based on the nurse's specialty. Although many doctors agreed to take care of the study participants separately from the clinical practice, they lacked the time to do so. In spite of the doctors' workload reduction by introduction of the CRC concept, their views regarding clinical trials for drug approval remain conventional. Further refinement in the support process by CRC should be considered in our hospital, and the views of the doctors should be investigated in a larger study, in order to promote clinical trials for drug approval in Japan.

Principles of Pharmacology: Basic Concepts and Clinical Applications

<i>Principles of Pharmacology</i>is intended as a concise reference book for medical and graduate students, residents, postdoctoral fellows, faculty members, and health professionals in medicine, pharmacy, dentistry, veterinary medicine, nursing, and public health. The volume is divided into sections, each the primary responsibility of a section editor or coeditors. As such, the strength of the text depends on the quality of the section editors and their selected authors. Many outstanding clinicians and scientists appear in the listing of "Editors, Authors, and Advisors"; this list is truly international and includes representatives from around the world. The international flavor is reflected in a supplement to the text about new drug approval in Japan. Most of this 1796-page text, however, is devoted to scientific and clinical aspects of pharmacology and therapeutics. The first section on general principles includes a comprehensive review of pharmacodynamics and pharmacokinetics and a discussion of drug development and the