Abstract
Purpose
This article describes postmarketing surveillance (PMS) study regulations and expectations of the regulatory agencies in 5 countries. With a focus on postapproval drug safety, there is a continuous need for understanding the benefit–risk profile of an approved drug. In addition to spontaneous adverse-event reporting, regulatory agencies seem to be more reliant on PMS studies. The opportunity to systematically monitor use in special populations, such as elderly patients and those with comorbid conditions, also presents itself during postmarketing use. Regulatory agencies in Japan, the Republic of Korea, and Mexico are requiring such studies as standards or conditions of drug approvals and license renewals. These studies are meant to be observational and noninterventional, over specified time periods. Studies are required specifically for following up treated patients in clinical practice, with the main objective of collecting safety data to further characterize the benefit–risk profile that was established during clinical trials and particularly in the country-specific population.
Methods
We reviewed and compared the published PMS guidelines and requirements in Japan, the Republic of Korea, the People’s Republic of China, India, and Mexico. Interpretations of the guidelines and requirements are included and are based on direct interactions with the different regulatory agencies.
Findings
We note that the different country PMS guidelines are at varying points in development. While some countries have more comprehensive guidelines, in others, the guidelines are still evolving. The similarities among guidelines include the requirements of the content and format of protocols, periodic reports, and interim reports of PMS studies. The differences in the requirements of PMS studies, such as sample size and study duration, are noticeable. These protocols are to be submitted, together with the respective risk-management plans, for approval by the regulatory authority prior to implementation of the study.
Implications
Conventional drug discovery and approval processes are well understood, and there are ample regulatory guidelines and International Conference of Harmonisation–based reference documents for understanding the path of the drug-approval process. Limited information is currently available with regard to the regulations and how PMS studies should be developed and evaluated. Some of the country-specific elements included can inform readers while they prepare to develop and implement PMS study protocols.
Key words
Introduction
Postmarketing surveillance (PMS) studies involve systematic monitoring of medications while they are used in clinical practice. Monitoring of medications while used in standard clinical practice is in contrast to the controlled settings of premarketing trials, in which study conditions are rigorously controlled. Although randomized clinical trials, which minimize variability, are useful for assessing the efficacy of one drug versus another, they may not inform on the effects of a drug after it has been released for use in the general population. PMS studies can also provide valuable information on the use of drugs in special patient populations, which is not easily obtained from premarketing studies. PMS studies allow for the monitoring of populations underrepresented or not studied in clinical trials, such as elderly patients, pregnant or breast-feeding women, and patients with multiple comorbidities.
Thus, factors that contribute to the need for PMS studies include a better understanding of the effects of a new medicinal product in larger populations in clinical practice, and changes in the regulatory approval process. These changes are becoming mandatory in many countries where regulatory agencies are requesting additional postmarketing data that would show the continued safe use in the treated population.
Studies may be proposed voluntarily as a part of a marketing authorization holder’s (MAH) risk-management plan (RMP), or mandated by a country regulatory authority as a postmarketing commitment linked to obtaining the initial country regulatory approval.
Different regions and countries have specific requirements and guidance for postmarketing commitments and may name them differently (eg, postauthorization safety studies [Europe], PMS studies [Japan and the Republic of Korea (hereafter, Korea)]). While the overall intent of these studies may be similar, the approach to study design and execution can vary considerably. In Europe, the development of postauthorization safety study protocols is guided by the European Medicines Agency’s Guideline on Good Pharmacovigilance Practices, Module VIII—Post-Authorization Safety Studies (Guideline on Good Pharmacovigilance Practices (GVP) Module VIII - Post -authorisation safety studies (Rev 2) [EU] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf. Accessed 1 April 2017). Mandatory or voluntary studies conducted in the European Union under this guideline are not the focus of the present article. This article focuses on the rather specific and demanding requirements of PMS studies from the regulatory agencies in 5 countries (Japan, Korea, the People’s Republic of China, India, and Mexico).
Materials and Methods
We reviewed and compared the published PMS guidelines and requirements from regulatory agencies in Japan, Korea, China, India, and Mexico. Interpretations of the guidelines and requirements are included and are based on direct interactions with the different regulatory agencies.
Results
PMS Studies and Risk-Management Plans
While this article focuses PMS studies from different countries, it is important to understand the link between PMS studies and RMPs, which are also becoming a global requirement for medicinal products.
The concept of RMPs was developed through the International Conference of Harmonisation. The relevant guidance, International Conference of Harmonisation E2E,
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was adopted in November 2004 and implemented in the European Union in 2005. In the European Union, the most current Guideline Good Pharmacovigilance Practices Module V—Risk Management Systems (revision 1),International Conference on Harmonisation (ICH) Guideline—Pharmacovigilance Planning E2E. 2004. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2E/Step4/E2E_Guideline.pdf. Accessed March 8, 2017.
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dated April 15, 2014, describes RMP development and the process of identifying, characterizing, preventing, or minimizing risks related to medicinal products. Within the context of identified, important potential risks and missing information, described as safety concerns within the RMP, a pharmacovigilance (PV) and risk-minimization plan needs to be included in the RMP. Proposals need to be developed by the MAH as a part of the PV and risk-minimization plan to further investigate each safety concern and to minimize the risks. One of the major decisions of, and agreements between, regulatory agencies is whether routine PV activities are sufficient or additional PV activities are needed. Additional PV activities can include nonclinical studies, clinical studies, or noninterventional studies.Guideline on Good Pharmacovigilance Practices (GVP) Module V—Risk Management Systems [EU]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf. Accessed March 8, 2017.
While the specific items of an RMP are mandatory and the detailed plan contents vary by country, there is broad international agreement on the need for an RMP as an important PV-planning measure. Risk management Plans are submitted at the time of dossier submission usually begins at the time of dossier submission (eg, New Drug Application, Marketing Authorization Application (MAA)). The RMP establishes safety specification and evaluation of PV and risk-minimization activities, in addition to specifying time points for reporting results to country regulatory authorities. While the primary purpose of the RMP is safety surveillance, the RMP may also include plans for measuring efficacy/effectiveness that contribute to the continued evaluation of the benefit–risk balance throughout the lifecycle of the product.
Safety risk–management planning has evolved substantially over the past decade and has become a standard part of the drug-approval process in some countries. However, despite the common goal, the individual regulatory requirements of each region (eg, the European Union, Japan, Korea, Mexico) can differ in practice. Table I lists the key risk-management guidance for the European Union, Japan, Korea, and Mexico.
Table IGuideline on RMPs.
| Territory | Regulatory Agency | Guidance document | Circumstances Requiring RMP or RMP Update |
|---|---|---|---|
| Europe | EMA | GVP Module V—Risk Management Systems 2 Guideline on Good Pharmacovigilance Practices (GVP) Module V—Risk Management Systems [EU]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf. Accessed March 8, 2017. | With all new marketing authorization applications; With applications involving a significant change to an existing marketing authorization, including new dose formulation, new route of administration, new manufacturing process of biotechnologically derived product, pediatric indication, or other significant change in indication; At the request of the EMA or national competent authority when there is a concern about a risk affecting the risk–benefit balance; At the time of the renewal of marketing authorization if the product has an existing RMP |
| Japan | Pharmaceuticals and Medical Devices Agency | RMP Guidance 3 Risk Management Plan Guidance. 2012. [Japan]. https://www.pmda.go.jp/english/safety/info-services/drugs/rmp/0001.html. Accessed March 8, 2017. | At the time of submission of approval application for new drugs; At the time of submission of approval application for follow-on biologics; At the time of submission of approval application for generic versions of the proprietary drugs for which additional pharmacovigilance activities or additional risk-minimization activities; When new concerns regarding safety have been identified in the postmarketing phase |
| Mexico | COFEPRIS | Pharmacovigilance Guideline to Develop RMP Issued by COFEPRIS 4 | A drug is registered as a new molecule in Mexico; A potential risk has been identified; At the request of the health authority; For biotechnological (innovative and biosimilar), biologic, and orphan products; |
| Republic of Korea | MFDS | Guideline on Preparation of RMP for Pharmaceuticals Drugs 5 | May be prepared and submitted throughout the drug lifecycle (ie, preapproval and postmarket); Should be prepared before drug license application (it is recommended that the safety management supervisor get involved in early drug development); May be submitted with the pharmaceutical drug license application; At the request of the MFDS due to postmarketing serious adverse events (contents should be sufficiently discussed with the MFDS before submission) |
COFEPRIS = Federal Commission for Protection against Health Risks; EMA = European Medicines Agency; GVP = Guideline on Good Pharmacovigilance Practices; MFDS = Ministry of Food and Drug Safety; RMP = risk-management plan.
Various regulatory agencies require PMS studies to be included as a part of the RMP. These PMS studies are broad-based and include intensive safety data collection during use of a medicinal product in clinical practice. The studies can be a condition of new authorization or license-renewal applications and included as PV activities in the RMP. PMS studies are mandatory in Japan, Korea, and Mexico.
In some countries (eg, Japan, Korea), during the period of PMS study execution, the MAH is granted patent exclusivity and thus is protected from competition from generic products. This timeframe is called the reexamination period and ends with the MAH preparing a reexamination dossier for submission to the regulatory authority. This dossier is conceptually similar to a Periodic Safety Update Report (PSUR) for the full reexamination period, although there may be additional requirements and submission format may vary. Assuming a positive dossier review, the MAH maintains its license to market the drug in the country. Table II provides an overview of key items required for PMS per country guidelines in the 5 countries discussed in this article.
Table IIOverview of PMS requirements.
| Requirement | People’s Republic of China | India | Japan | Mexico | Republic of Korea |
|---|---|---|---|---|---|
| RMP | No | No | Yes | Yes | Yes |
| PMS | Yes | Yes | Yes | Yes | Yes |
| Reexamination period | No | No | Yes | No | Yes |
| PMS supervisor | No | Yes | Yes | No | No |
| QPPV | No | Yes | No | No | Yes |
PMS = postmarketing surveillance; QPPV = qualified person for pharmacovigilance; RMP = risk-management plan.
PMS Study Requirements in Japan
Early Phase Pharmacovigilance
In Japan, early phase PV (established in 2001) is a requirement and refers to the safety assurance activities occurring within the 6-month period after marketing authorization of a new drug has been obtained. Early phase PV includes routine safety reports, surveys, and reporting of adverse drug reactions (ADRs).
Early phase PV is enforced by the Pharmaceuticals and Medical Devices Agency (PMDA) as a condition of marketing authorization in order to ensure appropriate use (eg, contraindication, careful administration) of drugs administered in medical institutions. The surveys conducted in this period are also meant to foster prompt evaluation of ADRs and prompt actions for the prevention of serious ADRs. For the first 2 months after the first delivery of drugs to medical institutions, reports need to be prepared every 2 weeks, after which there need to be monthly reports, culminating in a final report to the PMDA after 6 months.
Reexamination
Reexamination is the period of time in which PMS studies and other obligatory surveillance activities are conducted and reported to the PMDA to demonstrate continued clinical usefulness of the drug. These activities must be performed in compliance with the guidelines on Good PMS Practice (GPSP) or Good Pharmacovigilance Practices, and Good Clinical Practice (GCP) or Good Laboratory Practice, depending on the primary objective. Companies must submit a reexamination dossier to show that the drug maintains a good benefit–risk balance when used in clinical practice.
The reexamination period designated by Japan’s Ministry of Health, Labor, and Welfare is outlined in Table III.
Table IIIReexamination period in Japan.
| Duration of Reexamination Period | Drug Type/Reason |
|---|---|
| 10 y | Orphan drugs |
| 8 y | New molecular entities |
| 6 y | New routes of administration and fixed-dose combinations |
| 4 y | Additional indications and new dosages |
Drug Use Results Surveys
In Japan, the GPSP ordinance mandates PMS studies, commonly known as drug use results surveys (DURSs). GPSP defines the approach for DURS conduct and oversight to ensure that there are appropriate and consistent data available to support the submission at the end of the reexamination period.
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A DURS is normally required by the PMDA as a condition of approval or, in some cases, may be required for addressing specific risk-mitigation issues.Because these studies are specialized observational surveys conducted under GPSP, their protocols are generally less stringent than are those of studies conducted under GCP. As an exception, some PMS studies from Japan, in special circumstances, may be interventional studies and would then be subject to the GCP requirements in addition to the GPSP requirements. Some key GPSP requirements include a GPSP supervisor role, and the unique site-management and monitoring practices.
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Types of DURSs
One or more DURSs are obligatory for all newly approved drug products under reexamination in Japan. During the reexamination period, data are protected; the development of generics is not allowed.
DURSs can be of 2 types: (1) specified DURSs, which pertain to effects in a specific patient population (eg, pediatric patients, geriatric patients, pregnant women); and (2) all-patient DURSs, which examine effects in all patients who are given a drug within a certain timeframe. All-patient DURSs are often required for orphan and/or oncology products to supplement the limited treatment sample sizes in clinical studies. All-patient DURSs enroll all patients given the drug during a certain time period. The number of DURS patients can be much larger than in conventional clinical studies, and although the characteristics of patients vary by population, patients can number in the thousands. In these cases, patients are potentially recruited across many sites.
Both types of DURSs are observational, noninterventional studies of the approved drug, carried out under standard medical practice conditions. As outlined in the GPSP regulations, the mandatory components of a DURS protocol include objectives, planned number of cases surveyed, survey methods, survey periods, items surveyed, and analyses.
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As this protocol is rigorously discussed and reviewed with the PMDA, there is little flexibility in design and format, and protocol finalization and approval are usually streamlined processes.In addition to DURSs, there may be a need for interventional postmarketing studies, which must be compliant with GCP and conducted by a clinical department.
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DURSs are mainly safety studies and largely do not investigate efficacy due to their observational nature as well as a lack of ability to assess source documents.When a New Drug Application dossier is submitted, a high-level plan of the DURS (eg, protocol concept sheet or synopsis) must be included in the RMP and contain information about the type and size of the survey. The PMDA will request additional survey information during the review cycle, especially in the 2- to 3- month period prior to the approval date. One month before the survey is to be executed, the final survey protocol and case-report form are submitted to the PMDA for approval.
PMS Study Requirements in the Republic of Korea
PMS studies in Korea fall under the Ministry of Food and Drug Safety (MFDS) and are subject to compliance with the Standards for Re-Examination of New Drugs, Etc (2015)
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. In Korea, PMS model requirements have many similarities to those in Japan, although there are also various differences unique to those in Korea. In Korea, they do not have a GPSP regulation or a GPSP supervisor role, but they do have a Qualified Person for Pharmacovigilance (QPPV) role that has certain regulatory obligations for PMS studies.A draft of the protocol must be submitted at the same time as the RMP, that is, the initial draft at the time of submission to the country agency, and the final version at least 1 month prior to product launch. Patients participating in long-term–use studies can be included in the protocol, but a separate long-term protocol must also be submitted.
Reexamination
In Korea, reexamination is the period of time during which PMS studies and other surveillance activities are conducted and reported to the MFDS to demonstrate continued clinical usefulness of the drug.
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Companies must submit a reexamination dossier within 3 months of completion of the reexamination period. Table IV outlines the various reexamination periods, depending on the type of drug being investigated.Table IVReexamination period in the Republic of Korea.
| Duration of Reexamination Period | Drug Type/Reason |
|---|---|
| 6 y | New molecular entity; Ethical drugs different from already licensed ones in terms of active ingredients or mixture ratios; Ethical drugs different from already licensed ones in terms of route of administration, while containing the same active ingredient(s) |
| 4 y | Ethical drugs similar to already licensed drugs in terms of active ingredient(s) and route(s) of administration, but distinctly different in added indications;Ethical drugs which are modifications of the structure, formulation, or indication of existing drugs; MFDS consideration |
MFDS = Ministry of Food and Drug Safety.
Types of PMS Studies
In general, there are 3 types of PMS studies: usage results study, special study and postmarketing clinical trial. A description of the studies is provided in Table V.
Table VPMS study requirements in the Republic of Korea.
| Study Type | Description |
|---|---|
| Usage results study | This is the most common type of PMS study, and the goal is to collect and prepare data on results of using the drug and establishing the safety and efficacy of the drug in routine clinical practice. Usage results studies may include special patient populations (eg, children; elderly patients; pregnant women; patients with hepatic or renal disorders), if possible, to compensate for any lack in special-population cases in clinical trials conducted prior to approval. |
| Special study | Confirms or verifies specific matters as established at the time of product approval; could be required if there is a need for obtaining additional information due to any problems discovered in the results of assessment and/or analysis of information gathered during the postmarketing PV activities. Conducted only if required by the MFDS. |
| Postmarketing clinical trial | Observes the clinical effects and investigates adverse events related to the details of regulatory approval to collect information related to safety and effectiveness during PMS. Conducted only if required by the MFDS. |
MFDS = Ministry of Food and Drug Safety; PMS = postmarketing Surveillance.
Patient Requirements
Unique to Korea, there is a minimum number of patients required for PMS studies. There are two patient quota options that can be applied to PMS activities: 3000 patients or more and 600 patients or more (Table VIII). In some instances, there may be a need for changing the total number of patients as specified in the originally approved protocol. The MFDS will accept this protocol change under the following conditions: (1) the domestic prevalence of the indications of the product under reexamination is significantly low; (2) a dose adjustment or drug combination is appropriate due to the nature of the drug/formulation; and (3) a dose adjustment or drug combination is justifiable, with objective and reasonable calculation of the number of patients. The number of patients can be adjusted after at least half of the period from the drug-approval date to the reexamination expiry date has passed. Adjustments can be applied until at least 1 year before the reexamination expiry. Reasoning and documentation to support adjustments must be submitted to the MFDS.
Table VISample-size requirements in the Republic of Korea.
| No. of Patients | Description |
|---|---|
| ≥3000 | New drug approved only in Korea; New drug developed outside of Korea and not yet approved in that country; New drug developed and approved outside of Korea <3 y prior; New drug developed and approved outside of Korea, has been used in <600 patients in that country |
| ≥600 | All other situations not described above |
PMS Study Requirements in the People’s Republic of China
Drug Intensive Monitoring
In China, policies for drug PMS, known as drug intensive monitoring, are still evolving, and the available guidance and overall approach are not as comprehensive as in the United States, European Union, or Japan. However, the basis for intensive monitoring has evolved over the past decade, and provisions for the ideas of postmarketing reevaluation and reregistration are delineated in China’s Food and Drug Administration regulations.
On approval, China’s Food and Drug Administration may set an observation period for any new drug. During drug intensive monitoring, new and newly imported drugs are actively monitored for assessment and understanding of potential ADRs/adverse events over an extended period of use. The typical duration of drug intensive monitoring is up to 5 years from the date that the drug was approved for production or import.
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During this period, the company conducting the drug intensive monitoring has patent exclusivity of the product.Letter of Safety Supervision Division of State Food and Drug Administration (SFDA) on Soliciting Opinions for Notice of Promoting Manufacturers to Enhance Drug Intensive Monitoring [draft] [People’s Republic of China]. State Food and Drug Administration (SFDA) safety letter no. 12. Issued March 25, 2013.
Table VII outlines the conditions and situations in which drug intensive monitoring is required and not required. A drug intensive monitoring protocol must be submitted to the local or national Center of ADR Monitoring within 60 days of marketing approval. If the document is not returned to the MAH with comments within 20 working days of submission, the drug intensive monitoring protocol can be implemented. Unlike in Japan, in China, the role of the PMS supervisor is not explicitly mandated.
Table VIIDrug intensive monitoring requirements in the People׳s Republic of China.
| Drug Intensive Monitoring Required | Drug Intensive Monitoring Not Required |
|---|---|
| Drugs within the new drug monitoring period of 3–5 y | Drugs pertaining to a state of emergency as declared by the president of the People׳s Republic of China or the state council |
| Drugs imported within 5 y, in which the active ingredient has not been previously marketed in China | Drugs related to the mitigation of public health emergencies |
| Drugs for which intensive monitoring is required by the provincial drug regulatory authority | When the drug reserve department or health administrative department of the State Council proposes a special review and approval of a drug |
| Other drugs with known potential safety issues | Other circumstances applicable to special review and approval |
Data Collection
There are three types of forms that may be collected as part of Drug Intensive Monitoring: Centralized Surveillance of Inpatients, Registration-Return Visit, Questionnaire (Table VIII). The form type also determines the method by which data are collected.
Table VIIIData collection in the People’s’ Republic of China.
| Form Type | Method of data collection |
|---|---|
| Centralized Surveillance of Inpatients | Focuses on inpatients of medical institutions such as hospitals. Physicians, nurses, or other trained medical staff collect information on drug usage and ADRs by observing and questioning patients currently receiving medical care. |
| Registration-Return Visit | Conducted by hospitals or other institutions equipped to monitor drug usage, such as pharmacies or family planning centers. Outpatients who use, or are about to use, the drug are registered and periodically contacted via phone or other means to track drug usage and ADRs. |
| Questionnaire | Conducted by medical institutions such as hospitals or pharmacies. Drug usage and ADR information is collected via questionnaires completed by outpatients or their physicians. |
ADR = adverse drug reaction.
All data for drug intensive monitoring must be collected through a validated medical institution, such as a hospital, pharmacy, family planning center, or drug rehabilitation center, at predetermined time points.
Populations Monitored
There are 2 types of populations that may be studied under drug intensive monitoring: (1) general population monitoring, which includes anyone who is taking the drug being studied (there are no specific inclusion/exclusion criteria for this type of study); and (2) specific population monitoring, which can be carried out concurrently with general population monitoring and includes special populations such as elderly patients, children, and pregnant women and studies any ADRs related to the drug being monitored. Unless there are special reasons required or approved by the regulatory authority, the general population should be monitored.
PMS Study Requirements in India
In India, regulations and standards for PMS studies and their related protocols are still being developed. In particular, observational PMS studies lack many of the guidelines specified in other regions, such as the United States, European Union, and Japan. The guidelines that do exist are found within Schedule Y,
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an amendment of the Drugs and Cosmetics Act, as well as in recent recommendations from the Central Drugs Standard Control Organization, the national regulatory body for pharmaceuticals in India. Schedule Y focuses primarily on the requirements of clinical trials but does speak to PMS, primarily via the development and submission of PSURs.Drugs and Cosmetics Rules 1945. Schedule Y Amendment, version 2005 [India]. http://dbtbiosafety.nic.in/act/Schedule_Y.pdf. Accessed March 8, 2017.
PMS Study Period
Most PMS studies in India are conducted over a period of 4 years. They are often required by the Drug Controller General of India in order to understand the effectiveness and safety of a drug in clinical practice. Besides studying previously unrecognized safety issues while investigating and confirming the safety profile, and the efficacy of marketed drugs in their approved indications, PMS studies in India may also explore drug–drug interactions, dose–response relationship, and morbidity/mortality rates.
Role of PMS Supervisor
A lead investigator must be assigned to the PMS study by the MAH. This person must be a medical officer or a pharmacist who is trained in the collection and analysis of data from ADR reports.
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Drugs and Cosmetics Rules 1945. Schedule Y Amendment, version 2005 [India]. http://dbtbiosafety.nic.in/act/Schedule_Y.pdf. Accessed March 8, 2017.
Study Types
Strict types of PMS studies are not specifically outlined in India’s regulations, but the perceived intent is that studies may be observational or investigational in nature and must be suitable for monitoring and collecting the data necessary for generating PSURs during the PMS period. PMS studies should try to incorporate special populations, if applicable, including children, pregnant or breast-feeding women, elderly patients, patients with renal or other organ system failure, and patients on specific concurrent medications. Additionally, special studies may be specifically planned or conducted to examine a known safety issue and then documented accordingly in the PSURs.
PMS Study Requirements in Mexico
In Mexico, Federal Commission for Protection against Health Risks (COFEPRIS) within the Ministry of Health is the regulatory authority for pharmaceuticals. Within COFEPRIS, the regulatory bodies that oversee clinical research are the National Center of Pharmacovigilance and the Commission of Sanitary Authorization. The National Center of Pharmacovigilance is responsible for the oversight of all PV activities, in addition to setting local policies in line with national and international PV guidelines. The Commission of Sanitary Authorization oversees all interventional clinical trials collecting efficacy data. The main standard guideline governing PV, including PMS studies, in Mexico is the Installation and Operation of Pharmacovigilance (2013) (Mexican official standard NOM-220-SSA1-2012, INSTALLATION AND OPERATION of PHARMACOVIGILANCE [Mexico]).
Prior to dossier submission for approval, there are potentially 2 or 3 different expected presubmission meetings with COFEPRIS, depending on the nature of the product (eg, for biologics, an extra meeting with the Subcommittee of Biotech Products is required). Through these meetings, it is expected that the RMP materials will be refined to minimize the need for changes after dossier submission. These RMP materials typically include the protocol for intensive PV study—the term for PMS in Mexico. As the first meeting may occur as many as 13 months (for a biologic) or 8 months (for a small-molecule or orphan drug) prior to submission, it is important to plan accordingly within the sponsor’s safety department.
Revision of the RMP and the other materials may be required during the review period, depending on agency feedback. In Mexico, product launch does not typically occur until at least 1 year after approval, as formulary negotiations are initiated at the time of approval. Exceptions are use in some private-paying patients. Generally, intensive PV studies are not initiated until the product is available on the market and at the institutions involved in the study. There is no PMS supervisor role explicitly mandated by COFEPRIS. Mexico does not have a specific reexamination concept as do Japan and Korea, but instead has a product-renewal period of 5 years, in which the MAH must submit a renewal application to COFEPRIS at the end of year 4 after approval in order to receive a renewed license at year 5. In Mexico, biannual reports and a final study report, in addition to conventional PSURs, are required to be submitted during the duration of intensive PV study.
Study Types
The type of study included in the RMP depends on the identified/potential risks for adverse events associated with the drug (Table IX).
Table IXPostmarketing surveillance studies in Mexico.
| Study Type | Description |
|---|---|
| Early postmarketing study | Required if after evaluation there are no potential/identified life-threatening risks or risks that might affect the benefit–risk balance of the product. |
| Intensive study | Mandatory in the RMP if there are potential/identified life-threatening risks or risks that might affect the benefit-risk balance of the product. |
PV = pharmacovigilance; RMP = risk-management plan.
Discussion
Globally, the need for the development and implementation of PMS studies is increasing. This need comes from regulations being adapted in different countries. It is recognized that, at the time of marketing authorization, information on the safety of medicinal products is limited due to the small number of patients in clinical trials compared with the intended treatment population. Thus, PMS studies are being required for the identification and further characterization of the known risks, or for the identification of new risks, of a medicinal product in clinical practice, particularly in the country-specific population. Information from PMS studies would also supplement would also supplement the information available from the global safety profile.
We note that country PMS guidelines are at varying points of development. The guidelines in Japan and Korea are more comprehensive, while the guidelines in China, India, and Mexico are still evolving. Although PMS guidelines vary with regard to implementation and conduct in the 5 countries discussed, the overarching objective is to monitor the safety profile of a drug in clinical practice in each respective country. Other similarities in guidelines include the requirements for the content and format of protocols, periodic reports, and interim reports of PMS studies. These protocols are submitted with the respective RMPs, and must be approved by the regulatory authority prior to the implementation of the study. PMS protocols submitted with RMPs are refined through review and consultation with regulatory authorities before approval.
The differences in the requirements of PMS studies are noticeable. For example, in Korea, sample-size requirements are very specific (ie, 600–3000 patients); however, in our experience, depending on the product, epidemiologic data, or product landscape, smaller but adequate sample sizes may be proposed and agreed on by the agency. Additionally, an all-patient PMS study is generally required. However, in Japan, a specific population-based DURS may be proposed. This approach may perhaps also be acceptable to other regulatory agencies but remains to be explored. The duration of PMS studies is also noteworthy; protocol execution typically starts immediately following product launch, although each case is unique and typically negotiated with the regulatory agency. In the countries discussed, the minimum period seems to be 2 to 3 years but extends as long as 6 years (Korea).
In some countries, there may not be any expectations of PMS studies, or a PMS study protocol may not be required until the time of approval and product launch or license renewal. However, in countries where there are requirements for PMS, considerable planning and preparation need to be put into place in advance for inclusion in the submission dossier and for successful approval, reexamination, and license-renewal procedures.
Conclusions
We understand that established country guidelines need to be followed to meet each country’s specific requirements for PMS. We also understand the needs for these studies and the burden to conduct such studies. In our experience, a harmonized approach for the development of federal-based protocols and operation, where possible, is an efficient way to meet these increasing demands. We recommend that pharmaceutical companies develop clear standard operating procedures, detailing the roles and responsibilities needed for the development, review, approval, implementation, and monitoring of PMS studies in order to meet regulatory expectations in a timely, consistent manner.
Conflicts of Interest
This research and its publication were financially supported by Shire Pharmaceuticals.
All of the authors are employees of, and own stocks/stock options in, Shire. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
Acknowledgments
All authors contributed to the design of this study and this article.
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Article info
Publication history
Published online: April 07, 2017
Accepted:
March 10,
2017
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
