Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

Assessment of the impact of Japanese-specific long-term safety data on new drug approval.

Under the International Council for Harmonization (ICH)-E1 guideline for drugs intended for chronic or repeated intermittent use in non-life-threatening diseases, data from 100 patients exposed for a minimum of 1 year are required to be included in the safety data base of a new drug application. In response to the recent globalization of drug development, the Ministry of Health, Labour, and Welfare of Japan requires that the data according to the ICH-E1 guideline should be collected from 100 Japanese patients by the administrative notice of Basic Principles on Global Clinical Trials (reference cases) by considering ethnic differences in safety between Japanese and foreigners. In this study, we assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports of new drugs from 2016 to 2020 that include safety data for 100 Japanese patients exposed to these drugs for a minimum of 1 year to see if the study data led to the detection of Japanese-specific safety issues. The result showed that the safety data from these patients provided only marginal value to identify Japanese-specific safety issues, and no drugs were subjected to regulatory measures. Based on these studies and the fact that Japanese-specific safety differences detected for a few drugs did not lead to adaptations of drug regulatory measures, we would like to propose not to make it a rule to collect safety data from 100 Japanese patients exposed at least 1 year, while keeping the ICH-E1 guideline.

Achievements and challenges of the Sakigake designation system in Japan.

The Sakigake designation system (Sakigake) has been launched to encourage the pioneered development of innovative new medical products for the effective treatment of severe illness in Japan, which allows leveraging the several advantages in prioritized consultation, rapid review, premium drug pricing and extended data-protection period. We retrospectively analysed the Sakigake products including drugs and regenerative medical products to clarify the achievements and the future issues in this system. From April 2015 to August 2020 (the first 5-year trial period of Sakigake), 37 products were designated, and 10 of those were approved in Japan in which 7 new active substances achieved the first-in-world approvals. Oncology, neurology and cardiovascular disease were the major therapeutic areas, and those 3 accounted for 75.7% of all products. Sakigake achieved some first-in-world approvals by the Pharmaceuticals and Medical Devices Agency/the Ministry of Health, Labor and Welfare of innovative new medical products, although in some therapeutic areas, there remains room in stimulating drug development.

Rationales of delay and difference in regulatory review by Japan, the USA and Europe among new drugs first approved in Japan.

AIMS: To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. METHODS: Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). RESULTS: Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. CONCLUSIONS: Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

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.

Exposure of drugs for hypertension, diabetes, and autoimmune disease during pregnancy and perinatal outcomes: an investigation of the regulator in Japan.

Assessment of perinatal effects of drug exposure during pregnancy after approval is an important issue for regulatory agencies. The study aimed to explore associations between perinatal outcomes and maternal exposure to drugs for chronic diseases, including hypertension, diabetes, and autoimmune disease.We reviewed 521 cases of adverse reactions due to drug exposure during pregnancy who were reported to the Pharmaceuticals and Medical Devices Agency, a regulatory authority in Japan. The primary outcomes were fetal and neonatal death and malformation of infants. Associations between perinatal outcomes and exposure to each drug category for hypertension, diabetes, and autoimmune disease were evaluated using logistic regression analysis.Of the 521 cases (maternal age: 15-47 years; mean 32.3 ±â€Š5.5), fetal and neonatal deaths were reported in 159 cases (130 miscarriage; 12 stillbirth; 4, neonatal death; and 13 abortion due to medical reasons), and malformations of infants were observed in 124 cases. In contrast to the trend of association between diabetes with or without medication and fetal and neonatal death (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.17-1.36), exposure to oral antidiabetics tended to be associated with fetal and neonatal death (OR, 4.86; 95% CI, 0.81-29.2). Malformation tended to be correlated with exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (OR, 2.98; 95% CI, 0.76-11.7). This association showed trends opposite to that of the association with hypertension itself (OR, 0.42; 95% CI, 0.18-1.02) or overall antihypertensives (OR, 0.42; 95% CI, 0.15-1.13). Occurrence of multiple malformations was associated with exposure to biologics (OR, 8.46; 95% CI, 1.40-51.1), whereas there was no significant association between multiple malformations and autoimmune disease with or without medication (OR 1.07; 95% CI, 0.37-3.06).These findings suggest that drugs of different categories may have undesirable effects when used during pregnancy. However, the regulatory database was not originally designed to evaluate the causal associations between drug exposure and adverse drug reactions. The limitations of spontaneous reporting systems should be carefully taken into account. Further studies are needed to elucidate the effects of individual drugs in each category on perinatal outcomes.

Guggulsterone, a plant-derived inhibitor of NF-TB, suppresses CDX2 and COX-2 expression and reduces the viability of esophageal adenocarcinoma cells.

BACKGROUND/AIMS: Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-κB (NF-κB) activation is a critical event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-κB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC. METHODS: Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of IκBα, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well. RESULTS: GS inhibited DCA-induced IκBα phosphorylation. GS and the NF-κB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction. CONCLUSION: GS suppressed DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE.

Statins directly suppress cytokine production in murine intraepithelial lymphocytes.

Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are known not only as cholesterol-lowering agents but also as anti-inflammatory mediators. However, their regulatory effect on intestinal mucosal immunity remains unclear. The present study examined the possible direct effects of statin on intestinal intraepithelial lymphocytes (IELs), the front line cells of the intestinal mucosal immune system. Murine IELs were isolated from the small intestines of C57BL/6 mice. IELs activated with anti-CD3/CD28 monoclonal antibodies produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 in significant numbers; however, they did not produce IL-5. Both simvastatin and lovastatin suppressed IEL production of IFN-γ, TNF-α, IL-2, and IL-4 in a dose-dependent manner, whereas 48-h treatment with high concentrations (5 × 10(-5)M) of simvastatin and lovastatin did not affect the number of IELs. The suppressive effect of the simvastatin was significantly restored by the addition of mevalonate, farnesyl pyrophosphate ammonium salt, and geranylgeranyl pyrophosphate ammonium salt, which are downstream metabolites of HMG-CoA. These findings suggest that statins have direct suppressive effects on the production of T helper 1-cytokines and IL-4 in IELs; these effects are associated with inhibition of the mevalonate pathway to some extent.

Norepinephrine suppresses IFN-γ and TNF-α production by murine intestinal intraepithelial lymphocytes via the ß1 adrenoceptor.

We examined whether norepinephrine (NE) had direct effects on cytokine production by murine intestinal intraepithelial lymphocytes (IELs), compared with splenocytes. CD3⁺ IELs and CD3⁺ splenocytes expressed α(1B), α(1D), α(2C), ß1, ß2, and ß3 adrenoceptors (ARs). NE significantly suppressed IFN-γ and TNF-α production by IELs and splenocytes ex vivo. The suppressive effects of NE in IELs were reversed by ß1 AR antagonist CGP-20712A, whereas those in splenocytes were reversed by ß2 AR antagonist ICI118,551. In IELs, ß1 AR agonist xamoterol mimicked the suppressive effects of NE. These results indicated NE regulates intestinal mucosal immune responses mediated by IELs via ß1 AR.

Impact of acid inhibition on esophageal mucosal injury induced by low-dose aspirin.

BACKGROUND AND AIM: Aspirin enjoys widespread use as an antithrombotic drug, but such ubiquity also increases the risk of gastrointestinal mucosal injury. Recent studies have shown that aspirin can also induce esophageal mucosal injury. We resolved to determine the intragastric pH value necessary to prevent aspirin-induced esophageal mucosal injury. METHODS: 15 healthy Japanese volunteers were dosed for 7 days in a four-way random crossover trial with 100 mg entero-coated type aspirin only once daily, 100 mg aspirin + 20 mg famotidine twice daily, 15 mg lansoprazole once daily, or 10 mg rabeprazole once daily. All subjects underwent endoscopy and intragastric pH monitoring on day 7. RESULTS: 7 individuals (46.7%) developed esophageal mucosal injury when ingesting aspirin alone. The incidence of esophageal mucosal injury was reduced however with concomitant dosing of aspirin and famotidine (26.6%; p = 0.193), lansoprazole (0%; p = 0.004), and rabeprazole (6.7%; p = 0.019). Among individuals for whom mean 24-h pH was >5.0 and who experienced pH <4.0 less than 40% of the time, none developed aspirin-induced esophageal mucosal injury. CONCLUSION: Acid inhibition achieved with a half-dose of a proton pump inhibitor effectively prevented development of aspirin-induced esophageal mucosal injury, whereas a standard dose of a histamine-2-receptor antagonist failed to achieve the same results.

Influence of different proton pump inhibitors on activity of cytochrome P450 assessed by [(13)C]-aminopyrine breath test.

Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.

Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy.

AIM: To investigate whether potent acid inhibition is effective in non-erosive reflux disease (NERD) refractory to standard rabeprazole (RPZ) treatment. METHODS: We treated 10 Japanese patients with NERD resistant to standard dosages of RPZ: 10 mg or 20 mg od, 20 mg bid, or 10 mg qid for 14 d. All patients completed a frequency scale for symptoms of gastroesophageal reflux disease questionnaire frequency scale for the symptoms of GERD (FSSG); and underwent 24 h pH monitoring on day 14. RESULTS: With increased dosages and frequency of administration of RPZ, median intragastric pH significantly increased, and FSSG scores significantly decreased. With RPZ 10 mg qid, potent acid inhibition was attained throughout 24 h. However, five subjects were refractory to RPZ 10 mg qid, although the median intragastric pH in these subjects (6.6, range: 6.2-7.1) was similar to that in the remaining five responsive subjects (6.5, range: 5.3-7.3). With baseline RPZ 10 mg od, FSSG scores in responsive patients improved by > 30%, whereas there was no significant decrease in the resistant group. CONCLUSION: NERD patients whose FSSG score fails to decrease by > 30% after treatment with RPZ 10 mg od for 14 d are refractory to higher dosage.

[A case of eosinophilic gastroenteritis accompanied with fasciitis of the extremities].

We encountered a very rare case of eosinophilic gastroenteritis accompanied with fasciitis of the extremities. The patient was a 28-year-old woman with epigastralgia, eosinophilia plus leukocytosis, massive pleural effusion and ascites, and thickening of the walls of the intestine. Increase of the eosinophilic fraction in her ascites led to a diagnosis of eosinophilic gastroenteritis. She soon developed resting pain in all limbs and MRI revealed fasciitis. Prednisolone was effective in treating both gastroenteritis and fasciitis.

Successful treatment of ulcerative colitis complicated by Sweet's syndrome by corticosteroid therapy and leukocytapheresis.

Ulcerative colitis is occasionally complicated by dermatological disorders presenting as extra-intestinal manifestations, including erythema nodosum and pyoderma gangrenosum. Sweet's syndrome is considered to be a rare cutaneous disease in patients with ulcerative colitis. To date, only 17 cases of Sweet's syndrome complicating ulcerative colitis have been reported in the English literature. Here, we report a case of a 41-year-old male who had been suffering from ulcerative colitis for 20 years. He was admitted to hospital with hematochezia, diarrhea and fever, and painful erythematous nodules on the face and arms. Histological examination of skin biopsies showed inflammatory cell infiltration composed mainly of neutrophils without evidence of necrotizing vasculitis, and the condition was diagnosed as Sweet's syndrome. The patient was treated with prednisolone and leukocytapheresis and the erythematous nodules on the skin, as well as the abdominal symptoms and endoscopic findings of ulcerative colitis, immediately improved. In this paper we report on this case and review the literature concerning ulcerative colitis and Sweet's syndrome.

Preventive effects of lansoprazole and famotidine on gastric mucosal injury induced by low-dose aspirin in Helicobacter pylori-negative healthy volunteers.

The preventive effects of lansoprazole and famotidine on low-dose aspirin-induced gastric mucosal injury in relation to gastric acidity were compared in healthy Japanese volunteers. Fifteen Helicobacter pylori-negative volunteers with different CYP2C19 genotypes were randomly administered aspirin 100 mg, aspirin plus famotidine 20 mg twice daily, or aspirin plus lansoprazole 15 mg once daily for 7 days each in a crossover fashion. Gastroscopy for the evaluation of mucosal injury based on modified Lanza score (MLS) and 24-hour intragastric pH monitoring were performed on day 7 of each regimen. Aspirin induced gastric mucosal injury (median MLS = 3). Lansoprazole significantly decreased MLS to 0, which was significantly lower than that by famotidine (MLS = 1) (P < .05). Medians of pH 3 holding time and mean 24-hour pH values with the lansoprazole regimen were significantly higher than those with famotidine (P < .05). No significant differences in MLS were observed among the different CYP2C19 genotype groups in any of the treatment regimens. In this 7-day study, lansoprazole appeared to be more protective than famotidine against low-dose aspirin-induced mucosal injury but a larger well-controlled study is necessary to establish a definitive clinical benefit.