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]]>1.0 Background
The implementation of the new medical device regulations (MDR) on 25th May, 2017 has presented medical device manufacturers with several drastic changes in the decades old regulatory framework of the European Union (EU). The new MDR has effectively replaced the previous medical device directive (93/42/EEC) of the EU and also the directives relating to active implantable medical devices (90/385/EEC).
The new MDR offered medical device manufacturers with already approved devices in the market with a compliance time of three years till 26th May, 2020, which is just around the corner. For certain medical device manufacturers, the new MDR offered extra time following the date of application which enables them to provide new products to the medical device market for a maximum extended time of four years. However, in this case, extra requirements would be applicable for this additional period of transition.
2.0 Objective of the New MDR
The new MDR has been passed with certain specific objectives in mind. The key objective here is to make a two dimensional impact in enhancing the safety of medical devices(Laege Middle Styrelsen, 2019), which are;
- Reinforcing the rules associated with placing new medical devices within the market.
- Increasing surveillance post the device’s availability in the market.
Implications of the New MDR for Medical Device Manufacturers
The new MDR warrants the need for conclusive and hard evidence that is based on data for existing as well as new medical devices(Lehmann, 2019). It has several implications and would essentially mean that medical device manufacturers have to;
- Setup systems for managing quality and risk.
- Consistently gather clinical evidence for their devices following its market release, to validate the effectiveness as well as safety of the device.
- Provide data reports on a new centralized electronic system which will be easily available to the public.
- Be responsible for determining devices that requires reclassification and those that require additional review by a notified body.
- Setup systems that encompass their financial obligations in the event of unwarranted harm that arises from a defective device.
With the new MDR in force, the objective is to reinforce the rules associated with clinical investigation of medical devices, with a view to improve the availability of valid clinical information. Manufacturers are expected to adhere to stringent regulations with regards to performance, quality and safety of medical devices that they provide.
3.0 Challenges for Medical Device Manufacturers
Under the new MDR, medical device manufacturers are expected to affect substantial alterations in terms of quality assurance, product development and data reporting. Enforcement of the new MDR would mean higher cost implications and extended time required for new product development. Further, the process of clinical monitoring and gathering evidence for recertification of existing products could also prove to be an expensive proposition. Having said that, there are four key challenges(Anastasi & Hill, 2019) that the new MDR poses for medical device manufacturers and these would include;
3.1 Reclassification
As per the new MDR, major modifications will be effected to the classification of medical devices. In this case, requirements would be largely evaluated based on risk it presents to patients. For instance, specific devices that will be used on spinal cord will move up the order from class II to class III. As a process, reclassification of devices will have to undergo expensive process of certification for new products and also recertifying products that are already in the market. The focus of the new MDR would shift from approval of product to its whole lifecycle, warranting higher clinical assessment prior to approval. This would no doubt substantially slow down the production of medical devices.
3.2 High Clinical Testing Needs
Another key challenge that manufacturers are confronted with pertains to the increase in requirements for clinical testing. Owing to reclassification, manufacturers in the past who were not required to execute clinical testing, now need to be able to do so. New regulations also necessitate a reevaluation of clinical data pertaining to devices that already exist in the market. In the event that the data does not match the new requirements, medical devices need to be put through additional testing for recertification. This further augments the cost of sustaining legacy devices.
3.3 High Demand for Notified Bodies
As of now, notified bodies (NBs) acted as consultants in facilitating medical device manufacturers to adhere to the requirements for CE markings. With the enactment of the new MDR, NBs will assume the role of enforcers who will assess all medical devices (other than IVDs), those that fall above class I. However, the shortage of NBs to evaluate devices, specifically in devices classes that are of higher risk, will lead to a delay in approval for products and slow the entry of a device into the market. Furthermore, timelines are bound to be increased considering that NBs have a huge volume of data to review. This in turn, would tend to increase costs on the whole.
3.4 Significance on Post-Market Surveillance
Under the new MDR, much stress is being laid upon post-market surveillance. This would comprise of preemptive monitoring of the performance of medical devices for yearly safety updates for devices falling in the high risk class, recertification and prompt reporting of incidents concerning device safety. This kind of intense monitoring and reporting for safety requires additional resources which would prove to be a strain for medical device manufacturers.
4.0 Compliance
The new MDR presents some disruptive changes that have far
reaching implications for medical device manufacturers. With the transition
period almost at end, there are several modifications that device manufacturers
need to enforce to ensure success of existing and new devices. The extent and
intricacy of the challenge presented by the new MDR would require device
manufacturers to bring about substantial changes in domains as vast as; data
reporting, product development, manufacturing procedures and quality assurance.
To comply with the new MDR, device manufacturers can strategize and conduct a
gap analysis to identify whether their existing devices comply with the new
MDR. Excellent leadership is vital to facilitate the smooth transition to the
new MDR while developing a strategy for execution that comprises of preset
timelines and techniques to monitor progress with regards to compliance.
Medical device manufacturers could setup a core leadership team that would
include experts from quality assurance, clinical or medical affairs, R & D,
regulatory affairs, manufacturing, labeling, biocompatibility, sterilization
and marketing. Members of the team need to establish an active communication
with NBs while setting project harmonization between product portfolios and
business units(Premier Research, 2019). On the other hand, medical
device manufacturers are approaching external entities (Contract Research Organizations) to acquire
support and guidance to ensure compliance(Lehmann, 2019).
- Anastasi, V., & Hill, K. (2019). The top four challenges under the new EU MDR and IVDR. Retrieved December 7, 2019
- Laege Middle Styrelsen. (2019). New medical devices regulations. Retrieved December 7, 2019
- Lehmann, J. (2019). Compliance In Focus. Retrieved December 7, 2019
- remier Research. (2019). Strategic Planning for Compliance With the EU Medical Device Regulation. Retrieved December 7, 2019,
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]]>In Brief
- This particular write-up presents a background about e-dossiers that are submitted to regional authorities by pharmaceutical companies for drug registrations.
- The write-up highlights the pre-requisites and procedures while submitting an e-dossier.
Introduction
Right from 1990, the International Conference for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has been consistently striving to develop a framework which is standardized with regards to drug registrations. The objective of such a standardized framework is to bring about a harmony to the maximum extent possible, the content and structure of the technical information furnished to lend support to marketing authorizations. Representatives from Japan, the European Union and the United States and from other regions that function as observers are instrumental in driving the ICH. The steering committee of the ICH during November 2000 had ratified guidelines which were established by the ICH M4 working group, elucidating the Common Technical Document (CTD) in order to register pharmaceuticals that were intended for use by humans (Bonn, 2007). This implied that the paper version of the CTD had realized Step 4 status, indicating that the ICH members had reached a consensus wherein each member was committed to integrate the ICH guidelines within the regulatory framework of each region. Culmination of this last step is termed as Step 5. Within the United States (US), the FDA has officially embraced the guidelines as laid down by the ICH as FDA guidance. Within Europe, Volume 2B of Notice of Applicants underwent modifications during 2001 to incorporate the CTD within the legislative system in Europe. From July 2003 onwards, it has been made mandatory for every applicant to submit paper dossiers in the EU, Japan and the US.
However, a growing need was felt for facilitating electronic submissions. The ICH M2 ESTRI (Electronic Standards for the Transfer of Regulatory Information) working group created the standard for electronic message exchange for CTD which was termed as the electronic common technical document (eCTD). The eCTD comes across as an electronic form of a CTD that was paper based. The eCTD specification outlines the criteria to take into account electronic submissions as technically acceptable. In addition, the standards as laid down by the eCTD outline the mediums to develop and convey an electronic submission that matches the CTD definitions (Bonn, 2007). The focus here is to offer the capability to convey the CTD from industry to a regulatory authority. Also, the eCTD considers the necessity to extend assistance over the entire lifecycle of an electronic submission or dossier. The eCTD standard founded on the initial version 3.0 specification realized Step 4 during October 2002, and is being executed across regions, escalating it to Step 5.
Therefore, the objective of this article is to outline the regulatory and procedural guidance for e-dossier submission.
Fundamentals of Electronic Submission
The specification for eCTD elucidates the format for the message and the procedure for moving submission documents and processing instructions to an agency system. Standards as laid down by the eCTD offers a medium to capture every interaction that occurs between agencies and industry, in such a way that it sheds light on modifications between multiple submissions. This lifecycle view of the submission can be realized with the help of the XML format. By using the XML format, it is possible to describe every document that is included within the submission. In addition, it also offers instructions to the system that receives the submission, thus enabling data management, which elucidates the submission. Such data is popularly known as meta data and examples of meta data at the level of submission comprises information pertaining to the submission type, the agency that will receive the submission and the applicants who submit (FAMHP, 2016). Examples pertaining to meta data at the level of document would comprise of information regarding the version, descriptive information as in name of documents and time stamps and language. On the whole, the ability of the XML to segregate content from structure holds the key in terms of its versatility and increasing popularity. It has several uses, enabling users to restyle and reformat to match diverse media types, recognize elements, reuse portions, exchange data and sustain and output several versions for the same document.
As an outcome, extra specifications have been setup by several regions on the basis of XML format for content in the eCTD standard. These are frequently replace document files that are unstructured (eg; -doc, -pdf, -rtf) with XML documents that are highly structured and exemplified by the FDA’s Study Tagging File (STF) or Europe’s electronic Application Form (eAF), in tandem with initiatives at labeling like the FDA’s structured product labeling (SPL) and EMEA’s product information management (PIM). This trend can also be viewed as a consistent extension of the eCTD standard making the submitted information largely granular and more in a position to be managed with ease by systems which are automated. This, more often augments the efficiency and quality of the process of regulatory review.
Acceptance of e-Dossiers
The NCA Medicines and Healthcare products Regulatory agency (MHRA) in the UK has been since 2005 accepting electronic submissions while the paper format has been completely stopped since 2007. As a matter of fact, MHRA has made eCTD a mandatory requirement. While Belgium has embraced eCTDs largely, they still accept other formats. The same holds true for the Netherlands, Norway, Germany, Sweden, France, Denmark, Ireland and Austria. For nations like Romania, Cyprus, Spain, Czech Republic, Finland, Iceland, Lithuania, Latvia, Poland, Bulgaria, Estonia, Greece, Italy, Slovak Republic, Hungary, Liechtenstein, Luxembourg, Malta and Slovenia, no information is available with regards to eCTD standards.
Conclusion
Application of the eCTD standard within the XML format tends to allow an applicant’s submission documents to be reused within diverse regional markets. The submission is made up with five key modules wherein the first module comprises of all documentation specific to the region. Exchange of this very initial module with a module pertaining to another agency enables a highly effective re-submission process across diverse markets, without feeling the need to modify the documentation or the meta data from the rest of the four modules. Yet another benefit is that by creatively utilizing XML meta data, it is possible to outline the table of contents in different manners, enabling an application to have views that are specific to discipline (for instance; clinical vs. chemistry), lifecycle views that are cumulative which reveals every document and its existing state, views that are specific to submission revealing only the delta amongst submissions, module specific views etc., every additional particulars encouraging assembly efficiency and reviews.
References
Bonn (2007). Electronic Submission and the MRP/DCP: How to Compile a Dossier That Will be Accepted at the European Agencies. [Online]. der Rheinischen Friedrich-Wilhelms. Available from: https://dgra.de/media/pdf/studium/masterthesis/master_benning_l.pdf.
FAMHP (2016). eSubmission Guidelines. [Online]. Available from: https://www.famhp.be/sites/default/files/downloads/eSubmission Guideline revision 2 13final30102015.pdf.
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]]>In Brief
- The new European Union (EU) post-market surveillance (PMS) plan would act as a detailed tool for benefit-risk evaluation for medical devices.
- If the PMS is appropriately structured and executed, the EU-PMS plan would act as an intrinsic player in setting up a novel framework for proactive safety evaluation of medical drugs and devices.
The Need for PMS
Post Marketing Surveillance (PMS) can be defined as the process of identifying and gathering information pertaining to medications or medical devices after it has been approved by the concerned authorities such as the Food and Drug Administration (FDA) in the US. With regards to medications, a systematic PMS process commenced way back in the early 1970s and since then, there has been a substantial increase in PMS. Drug and medical device monitoring following the process of approval has become mandatory for several reasons (FDA, 2020).
Way back in the past during the 1950s and 60s, the number of drugs in the market were very scant compared to today which made monitoring a rather easy process. In the present day, drug manufacturing has assumed magnanimous proportions and is being consumed at a very high rate. Several other factors that warrant the need for PMS pertains to the modifications in the approval process of the FDA.
Though the process of approval has weathered harsh criticism, the FDA has countered the criticism by setting up opportunities and mediums for patients who are in need of critical drugs (Onakpoya et al., 2016). As an outcome, it might not be possible to identify the risks (during the premarketing stage) involved in using certain drugs.
Post market surveillance is executed by several different organization types, as well as agencies. These would comprise of universities, private organizations, pharmaceutical manufacturers and consumer advocacy groups. The objective of carrying out a PMS might vary from case-to-case and on the basis of the viewpoint of the personnel who would be responsible to execute the surveillance (Pane et al., 2019). Recent instances in terms of safety issues within public health that revolved around medical devices have also accorded much emphasis on the necessity to enhance the European Union medical device regulation (EU-MDR). This was particularly in response to the public health concern that arose in 2012 from hip implants.
Total metal-on-metal hip replacements were carried out effectively amongst several patients. However, abrasions from metal-on-metal led to leaching and erosion of metallic particles into soft tissue (FDA, 2013). Thus, the metallic debris resulted in weakened bone and tissue around the implant and eventually caused the implant to fail and necessitated the need for further surgeries. In the same year, another instance that led to a scandal pertained to the poly implant prothese (PIP) breast implants. Women in excess of 400,000 received these PIP breast implants which were manufactured using silicone gel of industrial grade. This industrial grade gel was prone to rupture and caused irritation and inflammation (New york daily News, 2012). This further advocated the need for PMS.
PMS: What it involves
Considering that the process of drug approval comprises of phase I, II and III trials, post marketing trials are often referred to as phase IV trials. PMS comprises of a systematic monitoring of drugs and medical devices as they are utilized in actual real-world scenarios. This is in contrast to controlled clinical settings during pre-marketing Clinical trials wherein the conditions of the study are strictly controlled (David & Kim, 2019). Though randomized clinical trials (RCTs) that have the propensity to lower variability are beneficial in evaluating the effectiveness of one drug or device as compared to the other, they seldom provide appropriate information on the effects of the drug or device following its release in the market for use by patients.
PMS: What it offers
PMS offers information which is highly valuable with regards to utilizing drugs within special population of patients. The information that is provided would not be easily accessible from pre-marketing studies. Studies that involve an RCT that have been executed prior to marketing comprise exclusively of subjects who match the preset exclusion and inclusion criterion, thereby creating a population that is largely homogenous (Suvarna, 2010). The population that makes up potential users following the drug or device being released in the market is very different from the population that has been evaluated during the phase of pre-marketing.
For instance, RCTs generally do not include women participants who are lactating or those who are pregnant. Therefore, PMS is only the medium of acquiring information on teratogenic and mutagenic impact of drugs amongst humans (Jain & Rahul Chauhan, 2019). Other populations who stand to gain from PMS would comprise of patients having multiple comorbidities and the elderly. Akin to pregnant and lactating women, extremely old patients are also not included during pre-marketing trials. A drug might affect different populations in a different manner. For example, a 30 year old healthy patient might show a different effect as compared to an 85 year old adult with multiple health issues.
PMS Plan Outputs
EU-MDR, there is a need to have a specific PMS plan for every product within an organization’s product portfolio. All medical devices of all classes are expected to have a PMS plan whose scope would vary as per the complexity of the product and the risks it brings. The outcome of the activities pertaining to PMS would make an impact on the process of PMS during the lifecycle management of the device. Certain information derived from the PMS plan would be utilized to update other documents pertaining to PMS. An approach which is modular in order to structure the PMS plan contents would be highly beneficial in providing consistent updates to other information related to PMS.
The outputs from the PMS plan would result or impact diverse post-market documents. For instance, following a review of national registries (an aspect of the Post Marketing Clinical Follow-up [PMCF] plan), it is possible that a manufacturer might recognize a new issue in terms of safety with the product which might impact diverse post market documents; update to clinical evaluation report (CER), development of corrective and preventive actions (CAPAs), new training for users or submitting field safety corrective action (FSCA) (Pane et al., 2019).
References
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- David, S. & Kim, P.Y. (2019). Drug Trials. In: StatPearls [Internet]. [Online]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546595/.
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- FDA (2013). Metal-on-Metal Hip Implants. [Online]. 2013. Available from: https://www.fda.gov/medical-devices/implants-and-prosthetics/metal-metal-hip-implants.
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- FDA (2020). Postmarketing Surveillance Programs. [Online]. 2020. Available from: https://www.fda.gov/drugs/surveillance/postmarketing-surveillance-programs.
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- Jain, P. & Rahul Chauhan (2019). India’s New Drugs and Clinical Trials Rules: An Industry Perspective. [Online]. Available from: https://www.raps.org/news-and-articles/news-articles/2019/7/indias-new-drugs-and-clinical-trials-rules-an-in.
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- New york daily News (2012). EU to tighten medical controls after PIP breast implant scandal. [Online]. Available from: https://www.nydailynews.com/life-style/health/eu-tighten-medical-controls-pip-breast-implant-scandal-article-1.1169444.
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- Onakpoya, I.J., Heneghan, C.J. & Aronson, J.K. (2016). Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Medicine. [Online]. 14 (1). pp. 10. Available from: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.
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- Pane, J., Francisca, R.D.C., Verhamme, K.M.C., Orozco, M., Viroux, H., Rebollo, I. & Sturkenboom, M.C.J.M. (2019). EU postmarket surveillance plans for medical devices. Pharmacoepidemiology and Drug Safety. [Online]. 28 (9). pp. 1155–1165. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pds.4859.
- Suvarna, V. (2010). Phase IV of Drug Development. Perspectives in clinical research. [Online]. 1 (2). pp. 57–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21829783.
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]]>In Brief
- A novel process where European Medical Agency offers a new service.
- The service is focused around medical literature monitoring.
- This service is also a vital step to ensure that there is no duplication of negative reaction reports.
- This service came into effect from 1st September, 2015.
Service Insights
The European Medicines Agency (EMA) on 12th May, 2015 presented an official intimation of medical literature monitoring service and also proclaimed that adverse reaction reports would be not be required to be entered within the EudraVigilance. The entire thing came into effect from 1st September, 2015 onwards. Following the announcement, the EMA has published a list of active substances and also provided a reference to the journals that will encompass this novel service. Initially, the service was poised to be initiated by taking around a restricted number (50 active molecules) of active substances from 1st July, 2015 and was supposed to be full-fledgedly implemented by September, 2015. As per the EMA, a preset array of journals and reference databases would be utilized for this service (Joshi, 2015). These journals / databases would include:-
- EMBASE
- EBSCO which would encompass a range of resources, wherein the primary focus would rest on the usage of;
- Medline Plus
- International Pharmaceutical Abstracts (IPA)
- The Allied and the Complementary Medicine Database (AMED)
To say the least, medical literature could prove to be a highly significant source for information pertaining to suspected adverse reactions from medicinal drugs. It is being offered as a service to an industry sector that for active substances and literature covered through activities of the EMA, would no more be obligated to record information related to suspected negative reactions within EudraVigilance. Any independent instances of negative drug reactions that would be found within the literature would be openly made available to marketing authorization holders (MAH). This would enable them to add the same within their safety databases and adhere to the reporting requirements beyond the European Economic Area.
PMS: What it involves
Considering that the process of drug approval comprises of phase I, II and III trials, post marketing trials are often referred to as phase IV trials. PMS comprises of a systematic monitoring of drugs and medical devices as they are utilized in actual real-world scenarios. This is in contrast to controlled clinical settings during pre-marketing Clinical trials wherein the conditions of the study are strictly controlled (David & Kim, 2019). Though randomized clinical trials (RCTs) that have the propensity to lower variability are beneficial in evaluating the effectiveness of one drug or device as compared to the other, they seldom provide appropriate information on the effects of the drug or device following its release in the market for use by patients.
Avoiding Duplication
No doubt, medical as well as scientific literature is supposed to be a major source that offers information in terms of recognizing any suspected incidence of negative drug reactions for drugs that had been authorized in the European Economic Area (EEA).
In due accordance with guidance as outlined within the ‘Good Pharmacovigilance Practices (GVP) Module VI’, organizations that have been authorized for marketing are supposed to monitor medical literature. They were also expected to notify about individual instances of alleged negative reactions from medicines for which they held marketing authorization within the EEA. However, the outcome of such an action was that it resulted in efforts being duplicated by marketing authorization holders. The duplication was in terms of active substances that could be found in more than one medicine, as well as duplicate entries regarding such reports were made into EudraVigilance and national safety databases (Heads of Medicine Agencies, 2012).
Expected Outcomes
The European Medical Agency executes the task of monitoring medical literature and entering pertinent information into EudraVigilance with a view to;-
- Improve the overall efficiency in terms of reporting negative reactions.
- Present the pharmaceutical sector with a simplification.
- Enhance the overall quality of data by lowering the scope for duplication.
- Undertake efforts to ensure savings in resource for the pharmaceutical industry.
Extend support in terms of activities pertaining to signal detection by holders of marketing authorization and national competent authorities.
Legal Antecedents
Article 27 of Regulation (EC) No 726/2004 forms the background for the tasks of the EMA. As per regulations, it has been stated that;
- Selected medical literature will be monitored by the Agency for reports pertaining to suspected negative reactions to medicinal products that are inclusive of some specific active ingredients. The Agency will also publish the list of active substances that are presently being monitored and the relevant medical literature that falls under their purview.
- Pertinent information derived from the chosen medical literature will be entered into the EudraVigilance database by the Agency.
- An in-depth guide will be created by the Agency following due discussions with Member States, Commission and concerned parties, with regards to monitoring medical and scientific literature and entering the required information into the database of EudraVigilance.
In tandem with Article 107, paragraph 3 of Directive 2001/83/EC, it won’t be necessary for marketing authorization holders to report suspected negative reactions to EudraVigilance that have been mentioned in the listed medical literature as monitored by the EMA. This is particularly for products that comprise of active substances that find mention within the list of substances that are under scrutiny by the EMA.
At the same time, it is also imperative to keep in mind that marketing authorization holders would still be responsible to keep a track on every other medical literature and report any suspected negative reactions (European Medicines Agency, 2020).
Active Substances Included
An extensive array of active substances which also comprises of herbals, have been chosen on the basis of the medicinal product information that has been provided to the EMA in tandem with Article 57(2), in the second paragraph of Regulation (EC) No 726/2004. Mainly a large number of active substances that are known to exist in medicines and those for which a large number of marketing authorizations which were provided to diverse marketing authorization holders within the EEA fell under this service (European Medicines Agency, 2020).
The detailed list, largely of chemicals and substance groups which were herbal and subject to being monitored by the Agency is available in a separate document on the Agency website.
Advantage Marketing Authorization Holders
The introduction of this new service by the EMA is bound to make a humungous positive impact mainly on marketing authorization holders who exist and operate in the EEA. As per estimates, around more than 3,500 marketing authorization holders for substance groups stand to gain from this service. In addition, marketing authorization holders in excess of 640 under the herbal substance group would also stand to gain an advantage through this move by the EMA (Joshi, 2015; European Medicines Agency, 2020).
References
- European Medicines Agency (2020). Monitoring of medical literature and entry of adverse reaction reports into EudraVigilance. [Online]. 2020. European Medicines Agency. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/monitoring-medical-literature-entry-adverse-reaction-reports-eudravigilance. [Accessed: 23 March 2020].
- Heads of Medicine Agencies (2012). Guideline on good pharmacovigilance practices (GVP). [Online]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-good-pharmacovigilance-practices-module-vi-management-reporting-adverse-reactions_en.pdf.
- Joshi, P. (2015). EMA Launches Medical Literature Monitoring Services: To improve the safety monitoring of medicines by enhancing the quality and consistency of data. [Online]. 2015. Safety & Risk Management Blog. Available from: https://www.sciformix.com/safety-risk-management-blog/ema-launches-medical-literature-monitoring-services/.
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]]>Introduction
- PSURs are pharmacovigilance documents that provide risk-benefit balance assessment.
- The notion of PSUR is to offer a wide and complex evaluation of risk-benefit balance of a medicinal product.
- PSUR reporting first came into existence in 1992.
- Purpose of PSUR is to provide an update of global safety experience with a specific pharmaceutical.
- It is imperative to consult the guideline on good pharmacovigilance practices (GVP) while preparing PSUR.
- MAHs are supposed to submit all PSURs in EU to the central PSUR repository.
PSUR; What is it?
Periodic Safety Update Reports (PSURs) are nothing but pharmacovigilance Service documents that are intended to offer an assessment with regards to the risk-benefit balance of a specific medicinal product at time points that are predetermined, following its authorization. The key idea of the PSUR is to offer an extensive and vital evaluation of the risk-benefit balance of the product, while taking into consideration novel or emerging information related to safety in the context of increasing information pertaining to benefits and risks. The European Medical Agency as well as other national competent authorities evaluate information that is contained within PSURs to understand whether there were any new risks recognized for a medicine and or / if there has been a change in its benefit balance. With the help of a PSUR evaluation, it is possible to determine whether any additional investigation for a particular issue were required, or whether an action was essential to safeguard the health of the general public (for instance; an update of the information that has been offered to patients as well as healthcare professionals.
PSUR; Origin and Recognition
The notion of PSUR reporting is said to have taken root from 1992. It has found recognition and is noted at diverse platforms. This is also inclusive of the International Conference of Harmonization (ICH) and the European Union and it has been noted that PSUR reporting has not matched pace with the due developments that have taken place in pharmacovigilance literature search like electronic adverse event reporting, and planning for risk management.During the year 2010, an awareness of such type has led to alterations in European Legislation laying down the needs for PSUR reporting. On the basis of a study conducted in the past, regarding determinants of safety associated
regulatory actions for bio-pharmaceuticals, it was found that evaluations through PSUR contributed to around 38 per cent of post-authorization regulatory actions within a sample of bio-pharmaceuticals. Furthermore, during the year 2010, it was found by that around 64 per cent of selection of adverse drug reactions (ADRs) stemmed through PSURs. The said two studies scrutinized the contribution of PSURs to recognized safety signals, that do not offer any insight into the manner in which PSURs are responsible for the purpose of safety monitoring, or the percentage of PSURs that results in regulatory action.
PSUR; Purpose
The onus of keeping track of the bio-pharmaceutical products rests on the shoulders of Marketing Authorization Holders (MAHs), once they are in receipt of authorization for marketing. It is well-known that MAHs are continuously engaged in dialogue with regulators to make sure that the appropriate strategies are deployed to optimize the advantage to risk ratio of their products. One of the key tools that are put to use to enable the post-authorization communication amongst MAHs and regulators is the PSUR. The purpose of PSUR is to offer an update of global safety experience with a particular pharmaceutical. This also includes data from safety data from observational and interventional studies, spontaneous reports along with other information pertaining to safety[1].The purpose of PSUR is also to proactively analyse, present and assess novel or altering safety related data from any source assessed with regards to estimates of product exposure, though the overall coverage of data sources would have restrictions in terms of practice.
PSUR; Preparation
The preparation of PSUR is an arduous and intricate procedure and requires much care and consideration. Keeping in mind the fact that PSURs are supposed to be prepared by MAHs, it is imperative that they mandatorily consult the ‘guideline on good pharmacovigilance practices (GVP): Module VII – PSUR’. Further, to facilitate the proper and appropriate preparation of the PSUR, the European Medical Agency has created an explanatory note to GVP module VII, that all MAHs are expected to consult at the time of preparing periodic safety update reports. The proper preparation of the PSUR will tackle particular problems in the European Union evaluation procedure for products that are nationally authorized. However, the issues could also be applicable to products that have been authorized in a central manner.
PSUR; Submission
Legal necessities for PSUR submissions had been setup through regulation (EU) No 1235/2010. Directive 2010/84/EU and in commission implementing regulation (EU) No. 520/2012. The PSUR format adheres to the structure that has been outlined in the Implementing Regulation Article 35 and module VII of the guidelines of good pharmacovigilance practices (GVP) offers guidance on the preparation, submission and evaluation of PSURs. The particular format is mandated by law for nationally authorized products (NAPs) and centrally authorized products (CAPs)[4]. Marketing Authorization Holders are supposed to submit PSURs as per the data lock points that have been duly published within the EURD list. The legislation brings in derogation for routine PSUR reporting for specific products. Till such time that there is a particular condition within the authorization, or it has been mentioned to the contrary in the EURD list, there is no need for routine PSUR reporting,particularly for medicinal products that have been authorized as per the articles of Directive 2001/83/EC.
As on 13th June, 2016, it is necessary for MAHs for submit all PSURs within the EU to the central PSUR repository by utilizing the eSubmission gateway / web client. It is compulsory for MAHs to utilize the PSUR repository for centrally as well as nationally authorized medications, irrespective of whether it is following the single assessment of the EU or a purely national process of assessment.
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