FormalPara Key Points

This study was done to understand the scientific value of the mandatory observational postmarketing studies (PMS) that were conducted by Pfizer in Japan from 2000–2020 for Pharmaceuticals and Medical Devices Agency (PMDA) reexamination.

The analysis covers a large dataset of 79 PMS for 43 products in over 98,000 patients.

The PMS results were found to be consistent with prior global data, with no evidence of clinically meaningful differences in safety in Japanese patients.

No new safety concerns requiring regulatory action arose from any PMS.

1 Introduction

Following approval of a marketing application, regulatory agencies often require sponsors to conduct post-marketing studies (PMS) to address scientific questions for which data are unavailable at the time of approval, including assessment of safety and effectiveness of real-world use. These required studies are known by different terms in different regions but include postmarketing studies (PMS), post-marketing requirements (PMR), Pediatric Research Equity Act (PREA) studies, postauthorization safety studies (PASS) and postauthorization efficacy studies (PAES) [1,2,3,4].

Such studies typically address a specific regulatory uncertainty related to populations that were not studied in the original drug development program (e.g., patients with a particular disease severity or subtype, a specific comorbidity, children and adolescents, etc.). A PMS may also be required to characterize a specific rare and serious adverse drug reaction (ADR) or the safety or effectiveness of longer-term use than was studied in phase 3. When properly targeted to a valid scientific uncertainty, PMS can contribute important information to support benefit/risk of the drug product, but these studies can also be challenging to conduct and consequently innovative approaches to satisfy the regulatory requirements have been proposed [5].

Global drug development programs usually recruit participants predominantly from North America and Europe with relatively fewer participants from Japan or other countries in Asia/Pacific. In contrast to the USA and the European Union (EU), where postapproval studies are required only when the regulatory agency has a specific outstanding scientific question to be answered, in Japan, PMS are a regulatory requirement for almost all new drugs, often regardless of any specific scientific uncertainty, and tend to focus on accrual of a defined number of cases.

In Japan, the Pharmaceutical and Medical Device Act stipulates that postmarketing information for all new drugs or indications is collected for a predetermined period after approval to confirm its efficacy/effectiveness, safety, and quality. This is a statutory requirement that has been in place since the “reexamination” process was introduced in 1979 as a part of corrective actions against subacute myelo-optic neuropathy (SMON) incident caused by Ciba-Geigy’s clioquinol in the 1950s–1960s [6]. It stems in part from a concern that safety might be different in the Japanese population compared with the predominantly western populations studied in phase 3.

There are three main types of Japan PMS: drug use investigations (which are noninterventional and prospective and are also known as drug use-results surveys), postmarketing database studies (which are also noninterventional but may be prospective or retrospective), and postmarketing clinical trials (which are interventional). The drug use investigations are subdivided into general drug use investigation (GDUI, also known as general use-results studies), which is a general observation of use for a drug being prescribed in clinical practice in Japan, typically with a focus on adverse event reporting but may also include efficacy or effectiveness; special investigation (SI, also known as specific use-results studies), which is similar to GDUI but with adverse event(s) being investigated in specific type(s) of populations/conditions (pediatrics, elderly, pregnant women, renal or hepatic impairment, and long-term usage) and comparative investigations (with a comparator drug, also known as use-results comparison studies).

Although they are less burdensome than randomized controlled trials, Japan observational PMS still require a significant investment of personnel and other resources and characteristically take several years to complete given the number of patient accruals required. From the sponsor, colleagues from multiple different lines are needed to plan, execute, analyze, report, and submit each PMS. This includes colleagues working in project management, clinical development, biostatistics, data management, medical writing, medical affairs, safety/risk management and regulatory affairs, as well as site-facing field-based colleagues. Contract research organizations may be needed for the delivery of these studies. Hence, the overall cost to the sponsor in terms of headcount and study budget is considerable. There is also a burden on investigators for training and for data completion. Additionally, the PMDA needs to dedicate sufficient resources to review each PMS proposal and evaluate the results during reexamination. Despite the burden, only rarely has a sponsor’s proposal of no PMS been accepted by PMDA, with postapproval safety information obtained through routine pharmacovigilance in place of PMS.

The reexamination period typically lasts around 8 years for new drugs. At the end of this reexamination period, the marketing authorization holder submits a reexamination dossier, including the results of the PMS, together with other safety information obtained during the reexamination period, results of risk minimization activities, and so on. Three outcomes of the reexamination are possible: category 1 “usefulness is confirmed,” category 2 “usefulness is confirmed by a partial change in approval” (e.g., a product label update is required to improve benefit/risk), and category 3 “usefulness is not confirmed,” meaning that the product may not be sold, and the marketing authorization holder may be required to recall the product from the market.

Pfizer has a relatively large portfolio of products in Japan and has accumulated many years of experience conducting PMS and making reexamination submissions. Given the resource requirements for running these studies and considering that many are not designed to address any specific scientific uncertainty, it is important to understand what scientific value PMS studies provide. Therefore, this retrospective analysis of Pfizer PMS performed in Japan from 2000 to 2020 was carried out to determine if these regulatory-required studies have made an important contribution to our understanding of drug product benefit/risk.

2 Methods

A retrospective analysis was conducted of all PMS in Japan conducted by Pfizer over 2000–2020. The corporate clinical trial registry (CCTR) is the definitive library of Pfizer-sponsored interventional and noninterventional studies in support of regulatory and safety reporting, with data entry, management, and quality control governed by standard operating procedures. The CCTR was searched to generate a listing of all studies conducted by Pfizer with investigational sites located in Japan. To identify the relevant Japan PMS, all phase 1, 2, 2B, and 3 studies (i.e., preapproval studies) were eliminated from consideration. The resultant list was then further limited to studies that were closed, were without active recruitment, and had either completed or terminated (as no clinical study reports would be available for planned, ongoing, or cancelled studies). Studies that had sites in Asian countries in addition to Japan sites were included but those with sites in the EU or USA were excluded because USA/EU sites would not be used in a Japan PMS. The study titles were then reviewed for keywords indicative of being a PMS (e.g., drug investigation, special investigation, regulatory commitment plan, and PMR). Finally, studies were limited to those that had first subject first visit after 1 January 2000.

To conduct the analysis, study level results were sought from two sources, the Pfizer clinical study reports (CSRs) and the PMDA reexamination reports (RERs). For each study, the CSR provides a detailed record of the methods and results, including comprehensive information on safety findings [7]. The RER provides a concise summary of the PMDA’s reexamination review, including pertinent safety information from the PMS together with relevant data from other sources and PMDA’s overall evaluation.

The global document management system, which is the corporate repository of all documents for regulatory submission purposes (e.g., clinical protocols, clinical study reports, etc.), was searched for an English language CSR for each study; if the CSR was not available, a CSR synopsis was reviewed as an alternative, if available. Each CSR or synopsis was reviewed for key safety findings.

The relevant RER was obtained from the PMDA website (if available), translated into English by a professional translation vendor and reviewed for key safety findings and conclusions. Each RER is associated with one product and typically with only one indication, but an RER may discuss more than one PMS for that product/indication. Some products had multiple RERs (e.g., for additional indications that were granted separately, after the initial approval).

The safety findings for each product were compiled from the CSR of the studies and from the relevant RER. Data were analyzed descriptively. The primary analysis was conducted on a tabulation of the safety findings from the subset of PMS that had both an English CSR and a discussion of that PMS in the relevant RER issued by PMDA.

Since PMS are conducted primarily for safety purposes, not all include efficacy measures. When available in either the CSR or RER, the efficacy findings were also reviewed.

Reexamination outcomes were obtained from the RER obtained from the PMDA website and/or from corporate records.

3 Results

There were 1801 studies conducted by Pfizer with investigational sites located in Japan. After excluding nonrelevant study types (e.g., preapproval etc.), this yielded 609 studies. From these, 85 studies had titles with keywords indicative of being a PMS and 79 of these had first subject first visit after 1 January 2000.

3.1 Availability of CSR and RER

In total, 79 PMS were identified for 43 different drug products across therapy areas. Total enrollment for all 79 PMS was 98,035 patients. The number of studies by therapy area are presented in Table 1.

Table 1 Postmarketing studies by therapy area
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The 79 PMS included 34 GDUI studies and 45 SI studies, as presented in Table 2. All studies were observational in design (real-world use of the drug), and the results of the two types of studies were broadly comparable in safety reporting/ADR rates. There were no comparative investigation studies, postmarketing database studies, or postmarketing interventional clinical trials.

Table 2 Postmarketing studies by type
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No new safety concerns surfaced in any PMS assessed in this analysis. No additional risk minimization measures (RMM) activities were required for any of the 43 products, which were the subject of the 79 studies. In all cases, the reexamination outcome was category 1—“usefulness is confirmed.”

A total of 46 PMS had a CSR or CSR synopsis in English. One product was subsequently withdrawn from market (for reasons not due to safety). Of these, 44 RER were available and were translated into English, and 39 RER discussed one or more of the 79 Pfizer PMS in the CCTR. These 39 “relevant” RER covered 30 products. Five RER did not correspond to any PMS study in the Pfizer CCTR (e.g., due to a copromotion or codevelopment agreement, a partner company conducted the PMS instead of Pfizer).

There were 37 PMS with an English CSR (or synopsis) and a discussion of that study in a RER; these PMS comprised the primary analysis subset (40,470 patients). These 37 PMS were for 22 drug products and the mean sample size was 1725 for the 15 GDUI studies and 672 for the 22 SI studies. An additional 19 PMS are discussed in an RER, but an English CSR (or synopsis) was not available; these studies were the RER-only subset. For these 19 PMS, information about study findings could only be gleaned from the RER issued by PMDA. There were nine further PMS with a CSR (or synopsis) but no RER; these studies were the CSR-only subset.

The availability of CSR and RER from the 79 PMS and the analysis subsets are shown in Fig. 1.

Fig. 1
figure 1

Post-marketing studies by availability of clinical study report (CSR) and reexamination report (RER)

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3.2 Safety

In most RERs, the PMDA provided a simple text comment comparing the nominal overall ADR rate in the observational PMS to the overall ADR rate observed in the phase 3 trials. No statistical inferences were made or intended. In 31 of the 37 PMS in the primary analysis subset, the RERs noted an overall ADR rate that was nominally lower than in the phase 3 program. In only one PMS was the ADR rate noted to be nominally higher than in phase 3. For three PMS, the ADR rates were noted to be similar. For two studies in the primary analysis subset, PMDA did not mention the phase 3 ADR rate, and no comparative comment was made.

In the subset of 19 PMS that were not included in the primary analysis but did have an RER available (21,463 patients), PMDA stated in the RER that the overall ADR rate in the PMS study was numerically lower than the overall phase 3 rate in 16 of the 19 studies and was higher in 2 studies; for 1 study, PMDA provided no comparative statement. The remaining 23 PMS did not have a corresponding RER that was available.

Unlabeled ADRs (i.e., those not included in the currently approved product label and referred to as unexpected ADRs in the RERs) were reported in 28 of the 37 PMS in the primary analysis subset. In most cases, these were listed by preferred term, although in some RERs, only the aggregate number of unlabeled ADR events was provided. Common terminology criteria grading of the ADRs was typically not provided in the CSR/synopsis. In the subset of nine PMS studies excluded from the primary analysis but that did have an available CSR (7197 patients), unlabeled ADRs were reported in six of the nine studies. Overall, of 46 PMS with an available CSR or study summary, 34 (74%) reported one or more unlabeled ADRs. The remaining 33 PMS did not have an English-language CSR or summary for assessment.

PMDA’s discussion of unlabeled ADRs, in the RERs, focused only on those ADRs found in the postmarketing pharmacovigilance database for each product; the numbers of unlabeled ADRs found in the observational PMSs were typically small compared with those found through pharmacovigilance and were not addressed in the RERs. A total of 39 RERs were available for 30 drug products, and unlabeled ADRs from the pharmacovigilance database were discussed in all 39 RERs.

None of the unlabeled ADRs identified in the pharmacovigilance databases, or in the observational studies, raised any new safety concerns requiring specific regulatory action, as all reexaminations were categorized as category 1.

3.3 Effectiveness

PMDA’s conclusion regarding effectiveness of the drug product was provided for 42 of the 56 studies that were discussed in an RER (including studies without an available CSR). For 11 studies, efficacy was noted to be ‘acceptable’, with no comparison to previous phase 3 studies. In four studies, efficacy was noted to be higher than phase 3. In seven studies, efficacy was lower than in phase 3, but no efficacy concerns were raised by the results and no regulatory action was deemed necessary. In 20 studies, efficacy was noted to be similar or consistent with phase 3 results. The RERs did not comment on effectiveness in the remaining 14 PMS that were discussed in an RER. An additional 23 PMS were not associated with an available RER; therefore, no PMDA comment regarding effectiveness was available.

4 Discussion

PMS have been mandatory in Japan for several decades and are a required part of the drug development process, postapproval. However, preapproval global drug development programs have evolved to be far more comprehensive than in the past and global pharmacovigilance of drug safety has also evolved significantly. Therefore, it is reasonable to ask if mandatory PMS still contribute to the understanding of human drug benefit/risk in Japan.

The strength of this analysis is a large dataset extending over two decades with over 98,000 patients’ data covering a wide range of therapy areas. The 79 Japan PMS identified were conducted for 43 different products. For all products, the reexamination outcome was category 1, “usefulness is confirmed”, which means that based upon the PMS data, together with other data available during the reexamination period (e.g., pharmacovigilance), the products could continue to be marketed and that no critical updates to the product labelling were necessary.

Despite mandatory safety reporting in postmarketing observational studies, the ADR rate was generally lower than in the phase 3 clinical trials, which may be due to the less formal nature of the PMS studies and the relative lack of source data verification compared to that required for the phase 3 interventional studies. One or more new (unlabeled) ADRs were found in most of the postmarketing studies (74%) but not in all studies. By contrast, unlabeled ADRs were found in the postmarketing pharmacovigilance databases for all 30 products that were the subject of the available 39 RERs. PMDA’s discussion of unlabeled ADRs, in the RERs, focused only on those ADRs found in the postmarketing pharmacovigilance database for each product, rather than on unlabeled ADRs that might have been found in an individual study. This may reflect that the RERs are very concise documents in which the PMDA places more emphasis on global pharmacovigilance data with its much larger patient-years exposure, compared to the smaller postmarketing studies. However, none of the unlabeled ADRs in this analysis was considered to have had a meaningful impact on product benefit/risk since no additional risk minimization measures were required for any of the products.

GDUI/SI studies are designed to assess all adverse events in the Japanese population prescribed the drug per the product label, under conditions of routine medical care. The decision to prescribe is independent of the study and those patients studied are a subset of all Japanese patients receiving a prescription.

From the primary analysis subset of 37 PMS with a CSR and a RER and regardless of study type (GDUI or SI), there was no evidence that the Japanese population have meaningful differences in safety or efficacy to the global population studied in phase 3. This indicates that the J-NDA process consistently assures that benefit/risk is acceptable at the time of approval and that the PMS do not yield important additional insights as, generally, efficacy and safety in Japanese patients are similar to the global population. Consequently, despite the current statutory requirement for their conduct and despite updated guidance issued from the PDMA in 2018 focused on improving their scientific focus, efficiency, and methodology [8], the necessity of regulatory-required PMS in Japan should be reconsidered.

Instead, routine pharmacovigilance, which is already conducted for all drug products, could be employed as an alternative approach to the mandatory GDUI or SI. A theoretical advantage of a GDUI or SI study is that AE reporting is obligatory (versus spontaneous reporting in routine pharmacovigilance); however, our finding that routine pharmacovigilance identified greater aggregate numbers of previously unknown ADRs, compared with the GDUI or SI studies, suggests that this potential disadvantage may be outweighed by the far larger numbers of patients subject to routine pharmacovigilance. Kanmuri and Narukawa [9] also concluded that routine pharmacovigilance was more effective; the authors conducted a review of PMS performed for 150 products in Japan and found that safety-related changes to the product label were predominantly driven by routine pharmacovigilance and were only infrequently prompted by a PMS finding.

When there exists a particular scientific uncertainty about the product, on the part of the health authority, a study designed to answer a specific scientific question is an appropriate requirement. In such circumstances, novel methodologies such as utilizing electronic health records data [e.g., the Medical Information Database Network (MID-NET [10]) or Medical Data Vision (MDV [11])] or the global pharmacovigilance database may be a more efficient and robust approach for answering those questions rather than the usual uncontrolled prospective observational methodology of GDUI or SI with limited statistical power. In addition, the question should be asked whether this needs to be addressed in Japan or could potentially be addressed by a study in another region.

This study was a retrospective analysis for which there are several limitations. Importantly, it represents the experience of a single sponsor (Pfizer) for a specified time period (from 2000 to 2020), which may or may not be generalizable. The time limit was placed since PMS design and execution have been consistent over this period. All the PMS identified were either general investigations or special investigations. There were no data from interventional comparative investigations, other postmarketing clinical trials, or postmarketing database studies. There were also significant amounts of missing data, since the CSR and RER were not available for all 79 PMS and hence the primary analysis subset included only 37 PMS (47%), although some limited assessment of the nonincluded studies and RERs was performed. Data were missing because not all RER are available on the PMDA website and because, over time, some products were divested from Pfizer to other companies; CSRs for divested products and some legacy products are not available within Pfizer’s global document management system.

However, the impact of missing data is likely not significant. Given the consistency of findings from the primary analysis subset, the RER-only subset, and the CSR-only subset and since all products had a category 1 outcome, the PMS indicated that, together with other data available during the reexamination period, they did not yield important new insights impacting benefit/risk balance. In this regard, it must be acknowledged that product labels could have been updated with new safety information prior to completion of the reexamination period, e.g., based on routine global pharmacovigilance data, annual safety reports, periodic safety update reports, or, in some cases, interventional clinical trials completed outside of Japan. Therefore, although all products were found to be category 1 by the Ministry of Health, Labour and Welfare, it is possible their reexamination outcome reflected product labels that had already been updated during the reexamination period, based on activities unrelated to the regulatory-required postmarketing studies.

5 Conclusions

The Japan PMS conducted by Pfizer yielded results, based on 98,035 patients, that were generally consistent with prior global phase 3 data from predominantly western populations. The analysis provided no compelling evidence that the Japanese population is meaningfully different in safety or efficacy or that the results of Japan PMS provided important new safety insights beyond the information available from routine pharmacovigilance, which was executed in parallel.

In Pfizer’s experience, the J-NDA process appears to consistently assure acceptable benefit/risk at the time of approval and mandatory PMS have not meaningfully furthered our understanding of product benefit/risk. While there may be instances of genuine scientific uncertainty related to a drug’s benefit/risk where a PMS is needed to effectively address that uncertainty, the mandate for conducting PMS in Japan for all newly approved drugs (including additional indications) should be reassessed. Whether Pfizer’s findings are generalizable is not known, and the perspectives from other stakeholders (industry, academic, and regulator) are encouraged.