Pharmaceuticals And Medical Devices Agency Research Articles

Identification of approval conditions for orphan drugs for neurological disorders by the Japanese regulatory agency

ABSTRACTBackground: Orphan drugs are used to treat rare diseases. Since consistent criteria for regulating these drugs are not clarified, we sought to identify the regulatory requirements and trial design elements of clinical trials for orphan drugs approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.Research design and methods: We identified orphan drugs approved to treat neurological disorders during April 2006–March 2016, using PMDA data. We investigated characteristics of pivotal trials from drug labels and drug approval packages, and identified six elements of clinical trial design: use of controls, blinding, randomization, size, analysis type, and end point. The evidence for efficacy provided by the PMDA was also collected for each drug.Results: PMDA has approved orphan drugs for neurological diseases in a flexible manner. Randomized, double-blinded, placebo-controlled pivotal trials were not always included in the new drug application package. The PMDA tended to make a positive judgment decision when a controlled trial was performed in Japan, regardless of the existence of foreign data.Conclusions: We provide a review of the Japanese regulatory environment for orphan drug approval in the neurological field by assessing the characteristics of clinical trials for orphan drugs indicated for neurological diseases in Japan.

Similarity of Clinically Significant Neuropsychiatric Adverse Reactions Listed in Package Inserts between the Anti-influenza Drugs Oseltamivir and Amantadine (Possibility Attributable to Common Pharmacological Effects)

The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as "clinically significant adverse reactions", and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.

The Pharmaceuticals and Medical Devices Agency's Approach to Facilitate Risk Communication and Its Challenges

The issue of drug lag in Japan has been rapidly reduced in recent years, and newly approved drugs now become available on Japanese and international markets at the same time. In this context, the risk management plan (RMP) system was introduced in 2012. RMPs describe important safety concerns recognized by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) and marketing authorization holders (MAHs), as well as safety measures that MAHs request healthcare professionals (HCPs) to follow. The publication of RMPs is expected to support the sharing of drug risk management among HCPs during the postmarketing phase. In addition, to encourage risk communication between HCPs and patients, the PMDA website provides drug guides for patients and other information to promote proper understanding of drugs by patients and their families and enable them to identify serious adverse drug reactions at an early stage. However, the results of surveys conducted by the PMDA in FY2014 and FY2015 revealed low levels of awareness of RMPs and drug guides for patients in hospitals and other healthcare institutions. The surveys also showed that information regarding the proper use of drugs from MAHs and the PMDA was not incorporated into practice at healthcare institutions, resulting in the repeated release of identical safety alerts. To facilitate the increased utilization of risk communication tools, the PMDA has been providing and disseminating these tools through its website. This study addresses those efforts and the associated challenges.

Impact of demographic factors on the antidepressant effect: A patient-level data analysis from depression trials submitted to the Pharmaceuticals and Medical Devices Agency in Japan

A substantial and variable placebo response can cause unreliable findings in clinical trials designed to demonstrate the efficacy of antidepressants, and the high rate of failed trials represents a major obstacle in the development of new drugs for major depressive disorder (MDD). However, the influence of demographic and symptom factors on the antidepressant effect remains to be established. The purpose of this study was to estimate the magnitude of this influence. A patient-level meta-analysis of data from double-blind, randomized, placebo-controlled trials involving the use of antidepressants for adults with MDD was performed. Data from five confirmatory trials evaluating the efficacy of four antidepressants that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) to support new drug applications were pooled (n = 1898). The change in the total score of 17-item Hamilton Depression Rating Scale (HDRS17) was the primary outcome of interest in our analysis. The changes in the total HDRS17 score in both the antidepressant medication group (ADM) and the placebo group (PBO) increased in relation to baseline symptom severity. Among older patients and those with a history of prior treatment with antidepressants, the changes in the total HDRS17 score decreased in ADM and remained static in PBO. There were no notable clinical symptoms that influenced the change in the total HDRS17 score. Baseline symptom severity, participant age and a history of previous treatment with antidepressants were suggested as moderators of the antidepressant effect. The drug-placebo difference in the estimated changes as a function of baseline symptom severity varied depending on the regression models used, and further studies are required to investigate appropriate models.

Proposal of Quality Management in Clinical Trials based on the Concept of ICH Guideline Q8

We investigated whether the basic concepts of ICH guideline Q8 “ Pharmaceutical Development” relating to the effective and efficient control of quality in drug development can be applied as a means for the effective and efficient implementation of audits carried out as a part of the quality assurance program for clinical trials in clinical development. We divided the clinical trial into 12 processes. Pharmaceuticals and Medical Devices Agency (PMDA) Inquiries from GCP On-site Inspections and Document-based Conformity Inspections, obtained from the PMDA on the basis of the information disclosure system, were categorized into the 12 processes. As our analysis targets, we chose the “ Revision of written informed consent form with regard to serious adverse events (SAEs)” process, which relates to patient safety, and the “ Examination/Observation/Assessment” process, which generates the highest number of inquiries. These two processes were further divided into several sub-processes. The inquiries were analyzed to tabulate the number of harms in each sub-process and to identify the nature of those events. We then identified the process parameters (PPs) of each process as well as deviations from said PPs (hazards), and tabulated the number of these incidences. We found that the number of harms attributable to said two processes were localized in specific sub-processes. Localization was likewise observed in the nature of the harms, the PPs relating to said harms, and deviations from said PPs. We also identified which sub-processes, the nature of harms,the PPs relating to said harms, and deviations from said PPs require management. Our findings suggest that the basic concepts of the ICH-Q8 guidelines can be applied to the quality assurance programs for clinical trials for the effective and efficient implementation of audits.

A Standard Intervention Practice to Promote Appropriate Lamotrigine Therapy by Pharmacists.

The dosage and frequency of lamotrigine administration for each patient must be prescribed carefully according to the disease, age, concomitant medications, and administration period. According to Pharmaceuticals and Medical Devices Agency (PMDA) reports, either the number of patients with adverse events caused by the inappropriate use of lamotrigine or the ratio of the patients who have benefited from the Relief System for Adverse Drug Reactions did not change even after the revision of the package insert in 2015. The procedure for auditing lamotrigine prescriptions was standardized to improve patient safety in our hospitals. The efficacy of standardization was evaluated by investigating the patients' records and prescriptions. A total of 77 patients treated with lamotrigine were examined to evaluate the appropriateness of the dosage and frequency of administration as well as the number of prescription enquiries made by pharmacists retrospectively. In addition, the presence of adverse events such as skin rash was examined using medical records. The number of inappropriate cases found and the prescription questions asked by pharmacists during the 24-month period before and after standardization were compared. The rate of inappropriate prescriptions after standardization was significantly lower than that before (12.1 vs. 29%; p<0.05). The rate of prescription questions raised after standardization was significantly higher than that before (37.0 vs. 1.7%; p<0.05). Moreover, there was no adverse event after standardization. Our standardization practice was effective to easily identify inappropriate prescriptions and provide physicians with the appropriate dosage or frequency of administration for the patients.

Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database.

Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3–71.4), 29.1 (23.5–35.9), 42.9 (32.3–57.0), 44.7 (32.7–61.1), and 38.6 (26.3–56.7), respectively. The medians (25%–75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3–314.0), 128.0 (27.0–279.0), 204.0 (44.0–660.0), 142.0 (41.3–344.0), and 16.5 (8.8–32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.

Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency.

To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012. We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action. We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8years (interquartile range [IQR], 3-26.5years). The median duration was 49days (IQR, 0-362days) from signal detection to tentative decision and 84days (IQR, 63-136days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations. Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process.

Clarifying the Discussion Points in New Drug Application Reviews for Approval in Japan by a Government Advisory Council.

In Japan, the Pharmaceutical Affairs and Food Sanitation Council (PAFSC) of the Ministry of Health, Labour and Welfare conducts discussions during the final stages of drug application reviews based on reports from the Pharmaceuticals and Medical Devices Agency (PMDA). Any disagreements or points of contention raised during these discussions can result in delays to drug approval. It is therefore important to characterize the points of discussion in the PAFSC meetings to optimize the process and enable more efficient drug approval reviews in Japan. We investigated the recorded minutes of PAFSC meetings concerning 229 drug applications (comprising 164 new drug applications and 65 supplemental applications) between fiscal years 2012 and 2014. The discussion points were characterized according to their main topics, and the frequency of each topic was examined. Clinical trials were the most frequent topic of discussion. Issues concerning package inserts were also prominent because many required reconsiderations and follow-up after council meetings. In particular, additional precautions and further clarification regarding drug indications and dosage were major points for reconsideration and follow-up. The review process may be improved if the points identified in this study are taken into consideration during the drug review process by the PMDA.

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control.

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles.

Next-generation sequencing–based clinical testing for lung cancer in Japan

: The development of targeted therapies for lung cancer based on the presence of corresponding specific biomarkers has highlighted the need for molecular diagnostic tests capable of the analysis of multiple actionable genetic alterations in a single tumor sample. Amplicon-based next-generation sequencing (NGS)—as opposed to conventional Sanger-based sequencing—has been introduced to facilitate the performance of multiple genomic tests with small amounts of tissue. In Japan, several institutions including the National Cancer Center and university hospitals have initiated NGS-based clinical testing for cancer patients and are able to provide access to investigational drugs or approved targeted agents matched to detected molecular alterations. However, no NGS system has yet been approved for the detection of somatic mutations by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. Further development of precision medicine in clinical practice in Japan will require changes to the medical curriculum to support the interpretation and annotation of NGS data. In this review, we introduce NGS-based clinical sequencing projects that are ongoing in Japan—in particular, those focusing on lung cancer—and we discuss issues relating to the integration of NGS into clinical practice.

Next-generation sequencing–based clinical testing for lung cancer in Japan

The development of targeted therapies for lung cancer based on the presence of corresponding specific biomarkers has highlighted the need for molecular diagnostic tests capable of the analysis of multiple actionable genetic alterations in a single tumor sample. Amplicon-based next-generation sequencing (NGS)— as opposed to conventional Sanger-based sequencing—has been introduced to facilitate the performance of multiple genomic tests with small amounts of tissue. In Japan, several institutions including the National Cancer Center and university hospitals have initiated NGS-based clinical testing for cancer patients and are able to provide access to investigational drugs or approved targeted agents matched to detected molecular alterations. However, no NGS system has yet been approved for the detection of somatic mutations by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. Further development of precision medicine in clinical practice in Japan will require changes to the medical curriculum to support the interpretation and annotation of NGS data. In this review, we introduce NGS-based clinical sequencing projects that are ongoing in Japan—in particular, those focusing on lung cancer—and we discuss issues relating to the integration of NGS into clinical practice.

A Comparison of PMDA and EMA Consultations for Regulatory and Scientific Matters in Drugs and Regenerative Medicine Products.

The Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) have provided a wide range of regulatory and scientific consultation menus to cover any development stage of drugs and regenerative medicine products, respectively. The current study compares Consultations by PMDA and Scientific Advice by EMA in terms of consultation types, consultation performances, and specific consultation procedures with timelines. Each agency sets intensive but highly professional procedures and timelines in order to provide sufficient advice in a timely manner. Both agencies complete the consultation process for approximately 3 months while an application is reviewed by experts and close communication with the applicant is provided. Although PMDA and EMA have some differences of approaches to provide well-considered scientific opinions as quickly as possible, both agencies have made efforts to support the development of better products for patients. Sharing technical insights through consultation experiences will contribute to earlier access of patents to new products in both Japan and the EU.

Evaluation of the Efficacy and Safety of Direct Oral Anticoagulants in Japanese Patients—Analysis of Pharmaceuticals and Medical Devices Agency Data

Two forms of direct oral anticoagulant (DOAC) have recently been introduced: direct thrombin inhibitors (DTI; e.g., dabigatran) and factor Xa inhibitors (FXa; e.g., rivaroxaban and apixaban). Despite the advantages of DOACs over warfarin with regard to cerebrovascular complications, those associated with DOACs have been reported with the increasing use of DOACs. Nevertheless, little is known about real-world comparative efficacy and safety of DOACs. Cerebrovascular adverse events collected by the Pharmaceutical and Medical Devices Agency (PMDA) during 2014 were analyzed to describe and compare efficacy and safety among patients prescribed DTI and FXa. Thirty-six cerebrovascular events associated with DTI and 419 events with FXa were reported during 2014. Ratios of hemorrhagic to ischemic events were similar in both DTI (2.2) and FXa (1.9) groups, with hemorrhagic events exceeding ischemic events. Ratios of intracerebral hemorrhage to total hemorrhagic events in patients with FXa (0.84) were significantly higher than those taking DTI (0.48; P < .01), but ratios of subdural (epidural) hemorrhage in FXa (0.14) were significantly lower than in DTI (0.44; P < .01). Among patients developing cerebral infarction, ratios of embolic to total ischemic events among FXa (0.34) and DTI (0.31) were comparable, but no patients taking DTI developed atherothrombotic infarction, compared with patients taking FXa (ratio of atherothrombotic to total ischemic events = 0.15). The present study indicates that different drug effects on cerebrovascular events may exist between DTI and FXa. DTI may play important roles in reducing and preventing intracerebral hemorrhage and atherothrombotic events.

The Predictive Safety Testing Consortium: safety bio-markers, collaboration, and qualification

The Predictive Safety Testing Consortium (PSTC) is one of nine consortia comprising the Critical Path Institute (C-Path), a non-profit organisation launched in 2005 and dedicated to playing the role of a catalyst in the development of new approaches that advance medical innovation and regulatory science. C-Path achieves this by lead-ing teams that share data, knowledge and expertise resulting in sound, consensus-based science. PSTC is a unique, public-private partnership that brings pharmaceutical companies together to share and validate safety testing methods under the advisement of worldwide regulatory agencies, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The eighteen corporate members of PSTC share a common goal: to find improved safety testing methods and approaches utilizing fluid-based safety biomarkers which accurately predict drug-induced tissue injury. Specifically, the primary goal of PSTC is the qualification of novel translational safety biomarkers for use in early clinical trials in order to ena-ble safer investigations and development of new drug candidates. This manuscript describes the critical importance of improved safety biomarkers to the drug development process and the present state of the biomarker qualification process with regulatory agencies. In addition, the work that the PSTC and its collaborative partners have done and con-tinue to do to identify and qualify more selective and specific safety biomarkers is highlighted. Finally, successes in-cluding the recently adopted regulatory Letter of Support and ongoing efforts to better define the regulatory qualifica-tion process and an integrated translational safety strategy are also discussed.

PD-8-1 - Learn more, Go further at the Pharmaceuticals and Medical Devices Agency (PMDA)

In 2013, I joined PMDA where I have been engaged in the regulatory review process for new oncology products as a part of a multidisciplinary team. In this role, I also offer advisory services for clinical trials that support new drug applications (NDAs). My responsibilities at PMDA have utilized my background in medical oncology. My particular mission is ‘smart regulation' and the purpose is to deliver effective drugs to cancer patients with a great degree of safety and without unnecessary delay. With this mission in mind, I am continuing to learn by collaborating with my professional colleagues at PMDA and other regulatory authorities (FDA, EMA, Health Canada, TGA etc.), which enables me to acquire a more comprehensive knowledge of clinical research and a broader international perspective. As a global bridge between academia, industry and regulatory officials, I want to demonstrate PMDA's essential role in advancing innovative medical solutions to benefit cancer patients worldwide.

PCN46 - Patient Reported Outcomes In Japanese Oncology Products - Review Of The Pmda Labels

With the growing importance of value-based care, patient-reported outcomes (PRO) has been gradually incorporated into various areas of healthcare. This study focuses on PRO that may be used in marketing, by reviewing labels within oncology products from 2007-2016 in Japan. Oncology labels were identified by reviewing the Pharmaceutical and Medical Devices Agency (PMDA) postings of label approval and changes for the past 9 years (2007- February 2016). Labels, Patient guidance Form (PF) and Interview Forms (IF) were acquired from PMDA webpage and reviewed for all relevant products. The IF is used as a supplement to the label which provides additional information that will not fit within the package insert. The PF is a brief summary of the label providing patient-oriented information on drug use. Labels, PFs and IFs for 109 active ingredients (170 products) were identified and reviewed. 34 (31%) IFs presented PROs, whereas both labels and PFs did not contain any PRO data. PROs were most frequently reported in 2013 (n=12) and 2014 (n=8). “QOL” and pain were the most commonly mentioned PROs. 18 IFs provided details of PROs while, the remaining simply noted that “QOL” was measured as secondary endpoint. The EORTC (European Organisation for Research and Treatment of Cancer) was most commonly used to assess patients’ QOL, followed by FACT (Functional Assessment of Cancer Therapy) and other generic QOL measurement tools such as EQ-5D and HUI. For pain assessment, Brief Pain Inventory – Short Form (BPI-SF) and the Visual Analog Scale (VAS) were identified through the review. One-third of oncology products contained PROs in the IF. Although the number of PROs has increased, in proportion to the number of oncology drugs listed per year, fewer than half report measurement of PROs. More efforts are needed to increase the importance of PROs in Japan.

Comparison of Regulations for the Development of Oncolytic Virus Therapy in the United States, the European Union, and Japan.

Oncolytic Viral Therapy (OVT) is one of the novel approaches for treating cancer and has a preferable safety profile. If a response to the therapy can been demonstrated, it can become one of the main therapies for cancer. We conducted a comprehensive comparative analysis of regulations for OVT development in the United States (US), the Europe Union (EU) and Japan to confirm a perceived lag in OVT development activities in Japan and explore its regulatory basis.Clinical development of OVT has begun all over the world. However, most of the development has been conducted outside of Japan. The lack of OVT development was not caused by scientific reasons but rather regulatory reasons. In this context, this article focuses on the regulatory dierences surrounding OVT throughout the developed world. In Japan, unlike the US, data from clinical development are required to obtain regulatory approval from Pharmaceuticals and Medical Devices Agency (PMDA); in other words, data from clinical research are not enough. However, in the US, data from either clinical development or clinical research can be utilized for new drug applications. In addition, Japan ratified the Cartagena Protocol, which demands special procedures for the use of viruses, which are key to OVT; the US need not follow these procedures as it did not ratify the Protocol. In short, in order to stimulate the development of OVT in Japan, we should harmonize our regulations on OVTwith those of the US and EU.https://doi.org/10.21423/jrs-v04n04p001 (DOI assigned 5/14/2019)

Role of Lateral Hypothalamic Orexin (Hypocretin) Neurons in Alcohol Use and Abuse: Recent Advances

Alcohol use disorders (AUDs) are chronic relapsing disorders with the modest efficacy of current medications. The US Food and Drug Administration (FDA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approval of the dual orexin (OX) receptor antagonist, suvorexant for the treatment of insomnia, may enable repurposing of this drug for the treatment of other diseases. Here, we summarize and reflect on the most recent research on the role of OX neurons in alcohol use and abuse. OX neurons regulate alcohol intake and seeking, although their involvement in different aspects of alcohol consumption/seeking, specific loci of action and interactions with other transmitter systems are still being clarified. Recent studies have identified anatomic loci of action and interactions between OX and other neuropeptides that drive alcohol seeking. Future studies are required to fully elucidate these behaviors, in which optogenetic and chemogenetic approaches may prove useful.

Similarities and Differences of International Practices and Procedures for the Regulation for Active Substance Master Files/Drug Master Files of Human Use: Moving Toward Regulatory Convergence

Purpose. A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers. Methods. We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines &amp; HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT–Medicines (Observer). Results. Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs. Conclusions. These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.