In this study, we identified the high reporting of ILD derived from mainly the ATC group L (antineoplastic and immunomodulatory) drugs. Furthermore, there is evidence of increased reporting during the re-examination period. As ILD is a targeted ADR for these types of drugs in a regulatory mandated use-results survey, we conclude that pro-active regulatory requirements contribute to the high reporting of ILD observed in Japan.
Grounds for High Rates of Reporting Interstitial Lung Disease
Role of the Use-Results Survey and Other Regulatory Aspects
The use-results survey is specified to characterize the incidence and the risk factors for the target ADRs. A priority item is selected among the ADRs detected in the pre-approval clinical trials based on a higher incidence and severity, and considerable attention is paid to the priority item in the survey during the re-examination. Interstitial lung disease was the priority item in the use-results survey that was mandated in the re-examination for gefitinib, erlotinib, everolimus, and nivolumab. These drugs revealed an increasing number of ILD reports after approval and/or high ratios of ILD reports to the overall reports. The ILD reports from the study for PKIs were 32% of the total ILD reports. In contrast, there were considerably fewer ILD reports of each herbal medicine compared with the top reporting L drugs. The herbal medicines are not subject to re-examination, because they are traditionally used with extensive clinical experience. Indeed, the labels for most of the herbal medicines have ILD mentioned only in the “clinically significant adverse reactions” section. The term ILD was added to their labels after use in a substantially larger and broader range of patient populations in the post-marketing period. Although there is a possibility of under-reporting in the spontaneous reports, the overall risk of ILD in the clinical setting of herbal medicine can be assumed to be much lower than in the oncology field. The patients with non-small cell lung cancer (NSCLC) who take antineoplastic drugs have often poor performance states and pulmonary fibrosis, which are the risk factors for life-threatening ILD, whereas the patients who take herbal medicines might be less susceptible, judging from their indications.
The solicited reporting process improves the quality of reports as compared with the spontaneous system, as standardized case report cards are utilized in the survey. While methotrexate has been the most frequently reported suspected drug of all drugs reporting ILD, their reports often contain scarce information in sharp contrast to PKIs. It is corroborated by the finding that the vigiPoint analysis revealed more ILD reports originating from studies on PKIs than on methotrexate. In addition, the early phase post-marketing vigilance that stimulates ADR reporting is required for new molecular entities. These regulatory processes for new drugs allow the capture of good-quality reports, which helps to make further regulatory decisions. The collected information of the new drug leads to the identification of risk factors and updates of product labels, which are shared with the labels for the generic drugs after the re-examination period expires.
Other regulatory processes may also stimulate ILD reporting. Inclusion in product labeling at the time of approval is suggested as one potential factor, as exemplified by the molecular-targeted drugs for NSCLC, specifically epidermal growth factor receptor (EGFR) inhibitors and tyrosine kinase inhibitors (TKIs). Many of them are found to induce ILD during their pre-approval clinical trials, resulting in the ILD risk being included in the label at the time of the market launch. The NSCLC drugs with the ILD warning tend to have high-reporting of ILD. In contrast, post-marketing labeling changes were found to affect reporting to a lesser extent as revealed by the example of herbal medicines in which there were comparable numbers of label changes in the observation period, but the accumulation of ILD reports was not high.
High Attention to the Molecular-Targeted Drug
Molecular-targeted drugs for NSCLC draw attention for a higher risk of ILD owing to a class effect of EGFR inhibitors and TKIs, as well as a higher incidence of pre-existing ILD in the disease [13]. Of note, the MAHs for EGFR-TKIs set independent ILD review committees of pulmonologists, chest radiologists, and pathologists to evaluate ILD-like cases to confirm ILD in the use-results survey [14, 15]. It helped to standardize the detection of ILD and discovery of risk factors. A thorough examination of ILD-like cases could lead to detecting the precise occurrence.
Clinical practice can change during the re-examination period and this can be reflected in the reporting rates for ILD. Protein kinase inhibitors are subject to active surveillance in the re-examination period, as they are new molecular entities. During the average 8 years of re-examination, clinical practice can shift, such as was observed with EGFR-TKI. The emergency safety information (Yellow Letter) issued in 2002 to warn about life-threatening ILD changed the clinical use of gefitinib; after the Yellow Letter, it was more carefully administered, and more suitable patients selected. The warning sections of labels for gefitinib and erlotinib indicate “close monitoring of the onset of serious adverse reactions such as interstitial pneumonia etc. under hospitalization or under similar conditions for at least 4 weeks after the start of administration”, despite the widely held view that solid oral dosage forms are used in ambulatory settings. In addition, the risk factors for EGFR-TKIs, such as a history of smoking, pre-existing pulmonary fibrosis, or poor functional status, were gradually elucidated [13], and chest specialists in general became well informed [16]. The use of EGFR-TKIs has been avoided for patients with risk factors. Those precautions could contribute to the decrease in ILD reporting in the latter half of the re-examination period.
The amount of gefitinib used in 2004 could be high judging from the high reporting of non-ILD ADRs, while the reporting of non-ILD ADRs were constant during 2005 and 2013, suggesting that the used amounts did not decrease. The ratio of ILD to all reports for gefitinib decreased in those periods. Likewise, reporting of non-ILD ADRs for erlotinib decreased during 2008 and 2015, suggesting a gradual decrease in use. The ratio of ILD to all reports decreased in those periods. The decrease could be interpreted as the comparatively better safety management of ILD.
Other Antineoplastic Drugs
The ILD-reporting patterns were constant for other antineoplastic drugs such as methotrexate, docetaxel, and gemcitabine. These drugs contribute to the accumulation of ILD reports given their longer availability for post-marketing use.
Regarding gemcitabine, the ILD report totals hovered around 90 reports per year after the re-examination period expired. While the ILD reports with the indication of lung cancer were constant during the observation period, the small increase in ILD reporting between 2010 and 2012 was due to the increase in the reports with the indication of pancreatic adenocarcinoma and stage 4 pancreatic cancer. In addition, the small increase between 2014 and 2016 was due to the increase in the reports whose indications were pancreatic cancer with distant metastasis and pancreatic cancer with concomitant use of paclitaxel formulated as albumin-bound nanoparticles. Given that the use of a drug changes with scientific progress in the treatment regimen, the regulators have to be aware of any increase even after the re-examination period has expired.
Consideration on Solicited Reports and Spontaneous Reports
There are interrelating effects between solicited reports and spontaneous reports in pharmacovigilance. We believe that pro-active regulatory requirements, such as the use-results survey during the re-examination period, in addition to the spontaneous reporting system, allow for immediate implementation of regulatory actions with potential clinical benefit. For example, the high reporting of ILD may be responsible for the early detection of the importance of the dosing sequence of EGFR-TKIs and nivolumab, which subsequently led to a series of Ministry of Health, Labour and Welfare notifications [17, 18]. The trigger was the accumulation of the solicited reports and the spontaneous reports of the EGFR-TKIs. In January 2018, the Ministry of Health, Labour and Welfare issued a relevant notification about an interim report of the all-case survey of osimertinib, where 33 ILD cases with a history of nivolumab were identified [19]. In February 2019, the label of osimertinib was updated based on the consideration that the final report of the all-case survey identified that the history of ILD and prior treatment of nivolumab were the risk factors for ILD in the treatment with osimertinib [20]. Given the higher incidence of pre-existing ILD in NSCLC, we must avoid misinterpretation that previously taking NSCLC drugs is a risk factor. The label update was based on the comparison with other covariates, such as previous chemotherapy treatment, World Health Organization performance status, and pulmonary radiation, identifying the risk with specificity [14]. In addition, the effect of previous nivolumab treatment was time dependent, suggesting the biological mechanism.
Meanwhile, the EGFR-TKIs and nivolumab programmed death-ligand 1 (PD-L1) blockade combination underwent scientific scrutiny. In an analogous situation, the durvalumab (another anti-PD-L1 antibody) plus osimertinib arm of the TATTON trial, ILD was markedly high [21]. There is growing concern that treatment with the PD-L1 blockade affects the incidence of EGFR-TKI-induced ILD in patients with NSCLC [22, 23], In particular, given that several EGFR-TKIs and PD-L1 pathway inhibitors are currently on the market, it is important to further elucidate the safest combination or sequence for the use of these therapies.