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

Abstract

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 Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn.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.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug safety communications (DSCs) are the primary tools for the rapid communication of drug safety information to healthcare professionals and patients. Characteristics and significance of DSCs by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have been demonstrated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the DSCs issued by the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) and are there any differences in the characteristics of DSCs issued by the PMDA/MHLW, the FDA, and the EMA?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study characterizes DSCs by the PMDA/MHLW from 1997 to 2022. Substantial serious ADRs related to DSCs are recognized after approval and are associated with critical label revisions and withdrawals. The number, contents, and range of new safety issues covered by DSCs differ among the three jurisdictions.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Regulators may need to discuss and harmonize safety‐related regulatory actions, including DSCs, for healthcare professionals and patients worldwide.

INTRODUCTION

The drug safety of novel therapeutics is continuously monitored because substantial safety‐related regulatory actions are required after approval. ¹ , ² , ³ New drugs are generally approved based on robust evidence of efficacy and safety; however, these data are usually generated in clinical trials on a limited population with a relatively brief treatment period. Various unknown or underestimated risks before approval can be revealed after approval with a rapid increase in the number of patients using the drug in clinical practice.

In Japan, important drug safety information, including adverse drug reactions (ADRs), is provided to patients, caregivers, and healthcare professionals through drug labels, which are the official documents for securing patient safety and appropriate drug use. The sponsors, under the supervision of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW), prepare drug labels, which are timely revised as necessary when new drug safety information is reported. However, the importance and urgency of drug safety information varies and may require a stronger alert than a standard label revision.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information that should be quickly and widely disseminated to healthcare professionals as well as patients. ⁴ , ⁵ , ⁶ In Japan, the PMDA/MHLW guides and distributes the Letters of Emergent Safety Communications (Yellow Letter) and the Letters of Rapid Safety Communications (Blue Letter), ⁶ in which the Yellow Letters are stronger warnings than the Blue Letters. The MHLW introduced the predecessor of Japanese DSCs, the Doctor Letters, in 1970. DSCs were developed in 1986 and transformed into the Yellow Letters in 1989. The Blue Letters were added to the Yellow Letters later to facilitate responses according to emergency level and DSC importance. Previous studies have characterized DSCs issued by the U.S. Food and Drug Administration (FDA) ⁷ and the European Medicines Agency (EMA) ⁸ ; however, knowledge of these activities by the PMDA/MHLW is limited.

This study characterized DSCs issued by the PMDA/MHLW in comparison with those previously reported by the FDA and the EMA.

METHODS

We retrospectively analyzed DSCs issued from July 1997 to December 2022 in Japan (Table S1). ⁹ , ¹⁰ Detailed information was obtained from drug labels, regulatory review reports. ¹¹ and sponsor press releases. We collected the number of prescribed patients by DSC issuance and the time from approval to DSC issuance for all DSCs and those for DSCs issued after introducing the Blue Letter category to address the difference between the Yellow and Blue Letters. ADR symptoms/diseases related to DSCs were classified according to medical specialties. We assessed whether the regulatory review report or the latest label before DSC issuance noted the ADRs that led to DSCs. Similar ADRs in a DSC were considered as one ADR. ADRs were regarded as noted in the drug labels or review reports if all ADRs leading to each DSC were described in these documents. Additionally, we investigated the association of DSCs with subsequent label revisions and withdrawals. DSC characteristics by the PMDA/MHLW were compared with those by the FDA and the EMA based on the literature review.

RESULTS

A total of 37 DSCs were issued on 41 ADRs for 33 drugs in 25 years (Table 1). The US or Europe approved 28 (84.8%) of the 33 drugs, and the remaining 5 were domestic developments. Most DSCs were related to non‐oncology drugs (30/37, 81.1%). Multiple DSCs were issued for edaravone (1 Yellow and 2 Blue Letters), ticlopidine (2 Yellow Letters), and sorafenib (2 Blue Letters). The frequency of DSC issuance by year demonstrated no consistent trend (Figure 1a).

TABLE 1.

Summary of drug safety communications in Japan from 1997 to 2022.

Characteristic	No. (%)
Medical specialty of drugs for DSCs
Oncology	7/37 (18.9)
Endocrinology	7/37 (18.9)
Cardiology	6/37 (16.2)
Infectious disease	5/37 (13.5)
Psychiatry	3/37 (8.1)
Anesthesiology	2/37 (5.4)
Neurology	2/37 (5.4)
Rheumatology	2/37 (5.4)
Others	3/37 (8.1)
Initial approval year of the subject drug
Before 1990	4/33 (12.1)
1990–1999	6/33 (18.2)
2000–2009	14/33 (42.4)
2010–2019	8/33 (24.2)
2020–2022	1/33 (3.0)
Not described in regulatory review reports	16/28 (57.1)
Not described in the latest labels before DSC issuance	12/37 (32.4)
Months between initial approval and DSC issuance, median (IQR)	19 (10–51)
DSCs led to label revisions
Any	36/37 (97.3)
Warnings	24/37 (64.9)
Contraindications	12/37 (32.4)
Dosage and administration	3/37 (8.1)
Patients with specific backgrounds	16/37 (43.2)
Important precautions	25/37 (67.6)
Drug interactions	1/37 (2.7)
Adverse drug reactions	27/37 (73.0)
Drug withdrawal	7/33 (21.2)

Abbreviations: DSC, drug safety communications; IQR, interquartile range.

FIGURE 1.

Differences between the Yellow Letter and the Blue Letter in Japan. (a) The frequency of the issuance of drug safety communications (DSC) by years demonstrated no consistent trend. The Blue Letter was first issued in 2002, and the majority of DSCs were issued as the Blue Letter afterward. (b) The number of prescribed patients by DSC issuance was not different between the Yellow and Blue Letters for all DSCs; however, these patient numbers were larger for the Yellow Letter drugs than for the Blue Letter drugs after introducing the Blue Letter category. (c) The time from approval to the DSC issuance was not different between the Yellow Letter and the Blue Letter for all DSCs and for those issued after introducing the Blue Letter category. BL, Blue Letter, DSC, drug safety communication.

The Blue Letter was introduced in 2002, and all letters since 2004 have been Blue except for one Yellow Letter of abnormal behavior related to oseltamivir. The number of prescribed patients by DSC issuance showed no difference between the Yellow and Blue Letters for all DSCs (Figure 1b). However, these patient numbers were larger for the Yellow Letters than for the Blue Letters for DSCs that were issued after introducing the Blue Letter category. The median (interquartile range) time taken from approval to DSC issuance was 19 (10–51) months, and the time to the Yellow Letter issuance was not different from that to the Blue Letter issuance (Figure 1c).

Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) ADRs related to DSCs, respectively, while 8/28 (28.6%) of regulatory review reports emphasize the need for assessing the ADR related to DSC through postmarket surveillance. Most DSCs resulted in label revisions (36/37, 97.3%), including warnings or contraindications as particularly important sections, and seven drugs were eventually withdrawn.

We revealed that some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA. The drug label structure differs between Japan and the US; however, the FDA DSCs were associated with critical label revisions, including boxed warnings (42/228, 18.4%) or warnings/precautions (103/228, 45.2%). ⁷ ADRs led to DSCs were not noted for 38/53 (71.7%) drugs at preapproval review for the EMA. ⁸ Most DSCs are issued on non‐oncology drugs among the three jurisdictions. Conversely, the scope of DSCs from the PMDA/MHLW demonstrated a difference compared with other regions. The PMDA/MHLW DSCs focus on ADRs, whereas the FDA and the EMA DSCs include guidance for appropriate use, withdrawals, and supply restrictions. ⁴ , ⁵ The FDA and the EMA issued DSCs with >20 reports/year and approximately 9 reports/year, respectively, whereas the PMDA/MHLW issued DSCs with <1.5 reports/year. ⁷ , ⁸ The period covered is different, though, the PMDA/MHLW DSCs in 1997–2022 only corresponded to the FDA DSCs for dabigatran, denosumab, drospirenone, and rituximab in 2010–2023 ⁴ and to the EMA DSCs for dabigatran and denosumab among drugs approved by the EMA in 2001–2010. ⁸

DISCUSSION

Substantial serious ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals in Japan. Some DSC characteristics in which non‐oncology drugs are major components and critical label revisions/withdrawals are required are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues covered by DSCs among these three jurisdictions were different. Our findings support the importance of continuous efforts to collect drug safety information after approval and suggest that regulators need to discuss and harmonize safety‐related regulatory actions, including DSCs, for healthcare professionals and patients worldwide.

Our study revealed that substantial ADRs leading to DSCs were unknown or underestimated before the PMDA/MHLW approval, which is compatible with the EMA DSCs. ⁸ These findings suggest the importance of harmonization for safety‐related regulatory actions where many drugs are simultaneously developed worldwide based on global clinical trials in recent years. Sharing the information of DSCs that was reported in other regions benefits patients and healthcare professionals, enabling them to know, observe, and treat or prevent ADRs, while if this is not achieved, an opportunity for appropriate prevention, detection, and treatment may be missed. However, each regulatory agency may have its policies or attitude to handle DSCs, and significant differences in the quantity and its roles were observed. Interestingly, most ADRs led to DSCs by the PMDA/MHLW are not seen in the FDA and the EMA DSC lists, whereas most new drugs approved by the PMDA/MHLW have been recently approved by the FDA or the EMA, ¹² and the postmarket pharmacovigilance system is similar among these three jurisdictions. ¹³ Further discussion and harmonization of DSC information among regulators may be beneficial for communicating with healthcare professionals and patients worldwide.

DSCs are issued for serious safety risks and are associated with critical drug label revisions and withdrawals. Most drug labels were revised after DSC issuance, and warnings or contraindications, which were particularly important sections in drug labels, were changed in many cases; these characteristics are similar to those of the FDA DSCs. ⁷ Additionally, we revealed that drugs with DSC were highly prone to withdrawal from the market in Japan. Taken together, DSCs are prepared for serious postmarket safety concerns and demonstrate a significant impact on withdrawal decisions.

The Yellow Letters are issued for ADRs that are more urgent and important than the Blue Letters. We revealed that ADRs related to the Yellow Letters involved more patients than those related to the Blue Letters; these difference between the Yellow and Blue Letters became obvious after introducing the Blue Letter category in 2002. The PMDA/MHLW defined the Yellow Letters and the Blue Letters ⁶ ; however, the difference in criteria for these two types of DSCs remains unclear. Our findings suggest that the Yellow Letters were issued for ADRs with a high clinical and social impact due to a huge number of drug uses.

Most DSCs were issued for non‐oncology drugs in our study, and these results were compatible with those issued by the FDA ⁷ and the EMA. ⁸ Serious ADRs related to non‐oncology drugs may be more prone to DSCs than oncology drugs because non‐oncology drugs are generally recognized as safer than oncology drugs. A previous report revealed that biologics, psychiatric therapeutics, and accelerated and near‐regulatory deadline approval were significantly associated with higher rates of postmarket FDA actions, including DSCs ¹ ; however, our analysis included only two biologics and three psychiatric therapeutics, and such an association was not observed.

The necessity for alerts to candidate drugs with comparable mechanisms of action is an important issue in DSCs. A Yellow Letter for olanzapine, a multiacting receptor‐targeted antipsychotic, was issued in April 2002 for the ADR of diabetic ketoacidosis/coma caused by elevated blood glucose levels. A Yellow Letter was issued in November 2002 for quetiapine, an antipsychotic medicine with a mechanism of action comparable to olanzapine, for the same ADR, and the drug label for quetiapine was subsequently revised. A Yellow Letter was issued in July 2000 for gefitinib for acute lung injury and interstitial pneumonia. Sorafenib, a drug similar to gefitinib, did not cause acute lung injury or interstitial pneumonia on its drug label. A Blue Letter was issued in December 2008 for sorafenib for acute lung injury and interstitial pneumonia, and the drug label for sorafenib was subsequently revised. These findings suggest that regulatory agencies need to conduct rigorous safety monitoring for drugs with mechanisms of action comparable to those for which DSCs have been issued. The issuance of DSCs for drugs with comparable mechanisms of action may reduce ADRs but could be criticized as “excessive regulation” because the occurrence of similar ADRs with similar drugs is uncertain. The necessity and appropriate timing of providing alerts to drugs with comparable mechanisms of action is an issue of DSCs that should be addressed in further studies.

This study has several limitations. First, we assessed the number of patients who used drugs associated with DSCs; however, the frequency of ADRs related to DSCs in real‐world data is unknown. Second, information on the data source is lacking in most PMDA/MHLW DSCs, which is important for the transparency of safety‐related regulatory actions. ¹⁴ Third, we could not find the proportion of withdrawal after DSC issuance in the previously reported DSCs by the FDA and the EMA. Fourth, we did not investigate the effect of DSCs on ADR prevention, although previous studies revealed that DSCs resulted in a change in prescriptions in Japan. DSC for denosumab‐induced hypocalcemia changed the physicians' attitudes toward the combination use of denosumab with vitamin D/calcium supplement. ¹⁵ Additionally, another study revealed that dabigatran use for patients with a specific background (i.e., elderly, renal dysfunction, receiving antiplatelet medication) was altered after the issuance of DSC for dabigatran‐induced bleeding. ¹⁶ The effects of DSCs by the FDA ¹⁷ and the EMA ¹⁸ on drug use have been reported elsewhere.

In conclusion, collecting drug safety information after approval is essential for detecting serious ADRs and providing the best available information to healthcare professionals and patients for drug use. Further DSC discussion and harmonization among regulators may benefit healthcare professionals and patients worldwide.

AUTHOR CONTRIBUTIONS

Y.Ta., M.T., and M.I. wrote the manuscript. M.T. designed the research. Y.Ta. performed the research. Y.Ta., M.T., H.M., R.T., M.M., M.I., and Y.To. analyzed the data.

FUNDING INFORMATION

This study was supported by the JSPS KAKENHI Grant Number JP21K18094 (Mototsugu Tanaka).

CONFLICT OF INTEREST STATEMENT

The authors declared no competing interests for this work.

Supporting information

Table S1

Tanaka Y, Tanaka M, Miyazawa H, et al. Postmarket safety communications on drugs approved in Japan: A 25‐year analysis. Clin Transl Sci. 2024;17:e13803. doi: 10.1111/cts.13803