Information on drug product safety is collected beginning before marketing approval and continuing after approval. Before approval, highly accurate information can be obtained through intervention studies (phase 1, 2, and 3 clinical trials) conducted in specific populations. After approval, safety information is primarily collected based on spontaneous reports and/or observational studies performed in daily medical examinations (Banerjee et al. 2013). Generally, in intervention studies, randomized, double-blind, comparative studies intended to verify hypotheses are conducted to obtain results with a high level of evidence. In contrast, in observational studies—sometimes beneficial for forming hypotheses because of potentially large sample numbers—control groups are virtually never included and the level of evidence of the results, therefore, is not very high.
Clinical studies prior to approval are usually conducted under a limited range of conditions, which has been referred to as the “5 toos” (too few, too simple, too narrow, too median-aged and too brief) (Rogers 1987) making it difficult to obtain all necessary safety information solely with such studies. In recent years, there has been more internationalization of clinical drug development programs. This has resulted in approval in Japan of new drug products for which only limited safety information on Japanese patients had been collected and evaluated (Iwasaki et al. 2012). Therefore, “collection of safety information at the postmarketing stage especially through observational studies” is becoming increasingly important. However, it has been reported that safety information collected postmarketing is limited because of underreporting (Hazell and Saad 2006; Macdougall et al. 2008). It is generally understood that expected and non-serious adverse reactions are more likely to be underreported. Bäckström et al. (2004) showed that at least 80 % of adverse reactions occurring postmarketing are not reported. Lopez-Gonzalez et al. (2009) attributed underreporting to such causes as “ignorance/preconceptions” (a belief that only serious adverse reactions need to be reported) and a “sense of security” (a feeling that only safe drug products are allowed onto the market).
Regarding regulation of postmarketing, in the European Union (EU) postmarketing safety monitoring systems have been strengthened, including by pharmacovigilance legislation implemented in 2012 (European Union 2011). In Japan as well, a guideline for a drug risk management plan (RMP) was issued in 2012 and, since April 2013, companies applying for marketing approval have been required to submit a RMP that contains postmarketing pharmacovigilance and risk minimization plans. These plans must account for risks, such as important identified/potential risks and missing information of the drug product (Risk Management Plan 2012). Japan is currently in the process of developing a new pharmacovigilance system.
In Japan, postmarketing surveillance (PMS) studies are required for newly approved drug products to ensure further collection of safety information in clinical settings. “PMS study” is a general term that encompasses both postmarketing observational (PMO) studies for re-examination, treatment outcome studies and postmarketing intervention (PMI) studies for re-examination, also known as phase 4 clinical studies. Each PMS study is conducted under contracts between the pharmaceutical company and medical institutions in accordance with Good Post-marketing Study Practice (GPSP) Ministerial Ordinance (MHLW Ministerial Ordinance No. 171, issued December 20, 2004).
For most new drug products or existing drug products for which additional indications have been approved, PMO studies for re-examination are routinely conducted to collect safety information after approval. “Re-examination” is a regulatory system specifying safety and efficacy testing of marketed new drugs within a certain period of time (normally 8 years) after approval to re-confirm drug effectiveness in clinical settings. This effectiveness is based primarily on the results of PMO studies for re-examination and spontaneous reports of adverse reactions. Because of this system, many PMO studies for re-examination are conducted postmarketing and are sponsored by pharmaceutical companies. However, most of these PMO studies for re-examination are conducted in a target sample size of 3000 patients without a control group. This sample size is regarded as sufficient to detect, with a 95 % probability, relatively rare adverse reactions occurring in about 1 out of 1000 patients (an incidence of 0.1 %) (Iwasaki et al. 2012). Neither the sample size nor the study purpose takes into account the characteristics of the safety information that was collected prior to drug product approval. For this reason, the safety information obtained from PMO studies for re-examination are seldom used for postmarketing safety actions such as revision of package inserts (Kanmuri and Narukawa 2014).
Conversely, in PMI studies for re-examination, the objectives of which may include collecting additional information not collected in the clinical studies conducted prior to approval, control groups are established and randomization is often performed. However, such PMI studies for re-examination are conducted only occasionally and for a limited number of new drugs. In fact, according to the ClinicalTrials.gov registry, there are few industry-funded PMI studies for re-examination being conducted in Japan.
Information collected in PMO studies for re-examination is structured, unlike that in spontaneous reports, and study plans are submitted in advance to the Ministry of Health, Labour and Welfare. In addition, PMO studies are conducted by medical professionals under contracts signed between the pharmaceutical companies and medical institutions. Therefore, PMO studies for re-examination are expected to collect safety data with higher quality and credibility compared with data collected under other observational studies. Nonetheless, in a questionnaire survey regarding PMO studies for re-examination administered to medical representatives of pharmaceutical companies, the representatives reported that non-serious and expected adverse reactions in particular are often underreported (Watanabe and Narukawa 2015). It was also reported that in PMO studies for re-examination, data collection is performed primarily by the investigators themselves with little support from other departments (Watanabe and Narukawa 2014).
With this as background, we focused on safety data collected in PMO studies in Japan, which are routinely conducted under the framework of the pharmaceutical regulation known as re-examination. The objective of our investigation was to identify differences in profiles of the drug product safety information collected through intervention studies and observational studies, and before and after approval. Our study addressed whether the issue of underreporting, generally considered as associated with observational studies, occurs in PMO studies for re-examination. In addition, we considered potential causes of such underreporting.