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I'm going to talk about the gvp model on the risk management systems this model will replace what is currently in volume 9 8 regarding the risk management system so as we all know the the you legal basis for the risk management system were introduced in 2004 with the revised regulation that came into force in November 2005 and in the regulation and the end in directive it was stated that there are some documents that need to be included in the application for a marking authorization and it says that the detailed description of the pharmacovigilance system and where appropriate of the risk management system that the applicant will introduce so this critical basis that we had in the past was not very clear what specific situations were required a risk management system so then in 2010 we have the revised legislation will related to the pharmacovigilance and the aim was to strength and improve the activities in pharmacovigilance in europe sorry so the major impact of this new legislation is basically is to reinforce the legal basis for the risk management system so in the future we will have to submit companies will have to submit a risk management plan for all new marketing authorization applications and also a risk management system can be requested in the post authorization phase if there are concerns the risk management plan is Hoover already mentioned is focused on the planning this planning should be prospective and dynamic and cording to the information that is becoming available and the activities should be proportional to the risks known there will be a key role of the new pharmacovigilance committee in relation to the assessment of the risk management and also into these updates the post authorisation safety and efficacy studies are integrated elements and may also be a condition of the marking authorization the summary of the risk management plan will be made publicly available because now only have the summary table that is included in the EPR but this summary will be completely different and is directed to the general public and there is also an in s requirement to monitor the effectiveness of the risk minimization and this is a responsibility not only for the martin authorization holders but also for the agency and for the member states to monitor how effective this risk minimization activities are being so the principles what we try to put in this gvp model so we have the implementing measure that is very high level we only have the format and the content defined so the details will be in the GDP model and these details are aligned more or less what we had in the IC H and we tried to merge what we had in the volume 9a and in the template of the risk management system and we also of course according to the experience that we'd gained during these six years and the feedback that we had from the stakeholders we try to keep what was worked and then change what was less good and improved so as we all know the purpose of the risk management plans is to describe what is known and unknown about the safety profile of the medicine and according to this knowledge what we plan to do to further characterize or identify the risks we also need to know according to to what is known and we need to put measures in place to minimize or to prevent risks and also very important to assess the effectiveness of those interventions we also need and this is new to document the need for efficacy studies in order to maximize the benefit risk of the product I think this template is very well known for all of us this is what we have currently so the the template is divided in two parts safety specification and pharmacovigilance plan and the second part on the evaluation of the need of risk minimization and if there is a need for additional risk minimization we will have a risk minimization plan so in the future this is the proposed structure of the EU RMP itself we structure in seven parts so in the first part we have the product overview where we have the administrative information the second part is the safety specifications that we had previously and here we organized these safety specification in models to be more flexible and so we can use some of these models in for example in the PSU ours and some models for example the technology of the disease will be the all the information will be done in the marking authorization application but is this will not change in the future so any future update some of the models don't need to be updated so they can be locked and you only submit what is new so this is very important to at least to simplify the work of industry and also for us to assess what is really new then we have the pharmacovigilance plan and the plans for studies on effectiveness and long term efficacy and we have now the risk minimization measure or risk minimization plan that is mandatory for all products even if there is no additional with immunization activities and we have this summary of the you RMP there are some situation and this is described very well in the gvp model that normally for example all parts of the RMP should be submitted however there are some exceptional circumstances for example in generics where some parts can be omitted for example we don't expect a generic to submit information or non clinical and clinical studies because they don't have that data so these parts should not be presented are not expected to be presented also for example if the reference product don't have any additional pharmacovigilance activity for example there is no study ongoing of course the generic is not expected also to conduct studies so the routine pharmacovigilance is enough so they don't need to present the pharmacovigilance plan in detail and also for the generics is very important because they will need to submit in the future for every new application the risk management plan so this risk management plan should be based on the safety concerns of the reference product and this will be a question I know how these generics will have access to the risk management plan of the reference products and you can search for example for the centralized products we have in the EPR the summary table of the RMP for the for the reference product if you don't have in the future we'll have these summary tables publicly available if not you can always request information on these but basically if you see the SPC of the reference product you will find what are the major concerns what are the risks of that product so the safety specifications part it seems that is very new but more or less is is the same what was previously in the safety specifications we just rearrange and reorganize the section so we have the technology of the disease and indication the non-clinical part the clinical trial exposures populations not study post authorization experience we have this additional EU requirements that are the same and then we have the identifying potential risk were where we merge three different sections from the previous safety specification that are the adverse reactions the interactions and the pharmacological class effects and then we have the summary of the safety concerns that will be the basis of the pharmacovigilance and the risk minimization plan so here in the in the model seven of the safety specification we have the identifying potential risks and as you can see in the GBP model now the risk management plans can be submitted they are not product specific but they can be submitted for example a company owns different marketing authorizations for the same active substance they can submit only one RMP covering multiple products with the same active substance however when we are doing these identifying potential risks we may need to structure the risks according for example if the risks are relative to the active substance for example if the risks are related to the specific formulation or the route of administration if they are specific for a target population because sometimes indications are different or for example if we have one active substance with the prescription and non-prescription status we can submit one RMP but we need to split and identify very well what are the risks of the prescription and non-prescription and then we have the pharmacovigilance plan here we put some clarification what is the aim of the pharmacovigilance plan so it's for to identify new safety concerns to further characterize to investigate potential risks or to know more about the missing information there is also clarification because sometimes there was confused between also in with the Assessors and also with the companies about these specific these questionnaires to follow-up specific adverse drug reactions so this is clear in the GBP that this is considered routine pharmacovigilance activity also for example in the previous guidance it was not clear for example the action plan for each safety concern sometimes the company presents the rationale and the objectives of the routine pharmacovigilance activity so this is clear that we don't need the companies to provide the rationale for the routine pharmacovigilance we only need to focus on the additional pharmacovigilance activities because the routine is mandatory and is referred in the pharma cohesion system Master File that no need to be repeated here in the risk management plan is very important to put a summary table of the additional pharmacovigilance activities and including also the expected dates of milestones because we need to track if the company is complying with these milestones and if not they need to provide a reason for the delay and we need to update also the RMP of course there is also this new thing that we can ask the companies for example when we have a cross effect we can ask different companies to join or to conduct joint studies together and this will be I think Savior will reflect this into the next topic and there is also guidance for example in this pharmacovigilance plan to include additional pharmacovigilance activity that sometimes are requested by individual member states after the RMP is approve at EU level when you go to your member to member states and times they ask additional studies sometimes to support the reimbursement and these studies if they are important to collect safety information they should be included in the RMP and then we have this new part is the plan for long-term efficacy and effectiveness follow-up this were required for pediatric medicines and advanced therapy additional products and now the legislation gives us the opportunity also to request these post authorisation efficacy studies when needed and this is for example when we have concerns about efficacy in everyday medicinal practice because clinical trials does not reflect the reality and for example when the knowledge about the disease or the clinical methodology has changed so we need to revise what we have approved in the past so in this part the companies should summarize difficulty and the basis of this efficacy for example to provide I don't know if it's possible in one page to summarize all the studies and the endpoints but we would like to have a short summary and also the following ELLs need to be discussed for example the applicability of difficulty data to all patients in the target population the factors that may affect the effectiveness of the product in the real life and the variability in benefits of treatment for subpopulations there is a guidance that is being draft on these post authorisation efficacy studies I don't know we're still drafting and discussing with the Commission about this and then we have the part 5 about the risk minimization plan so as I said this will be needed for all product independently if it's routine or additional if the RMP covers different products we may need more than one risk minimization plan for example if we have multiple legal status or cross triprotic areas or different risk for different target populations there is a clarification in the GDP what is routine for risk minimization activity and there is a separate model that is being draft about the effectiveness of risk minimization activities where we are going to explain more in detail what is additional risk minimization activity so on the contrary now we ask a justification to the companies when they propose additional risk minimization activities and of course the the focus on the effectiveness of the risk minimization activity is very important and there is also some guidance about educational materials that they should not be promotional there is advice for example to consult communication experts patient and health care professions that would be involved and they are the target of these materials with we will we may request a similar layout and content for example for different products with the same active substance like the generics and the final version is needs to be a proof obvious by the National competent authority and this as I said we will have a summary of the RMP that will be publicly available in the European web portal this will be written for lay reader and the information will include visiting in the disease epidemiology summary of the risk but is risk need to put in context of the benefits there will be a summary of the safety concerns a summary of the risk minimization activities and plans for post authorisation safety and efficacy studies and this summary of the RMP will be linked to the list of medicinal products subject to additional monitoring that will be published in the agency website and national component authorities we don't have yet any ID we don't have decided the final format of December of the RMP we are working on dit we have planned consultation in May with stakeholders including patients and healthcare professionals of course one size will not fit all we still have the summary table in the e pars but the objective of this summary is not the same of the summer that we have in the in the e part so basically this summary of the RMP will be based on the pathology of the disease on the on the safety concerns and the pharmacovigilance plan and risk minimization plan so we will try to provide and put the risks in context of the benefits will summarize the safety concerns in lay language and we will provide all the details about the plans of the studies and the risk minimization activities so in conclusion what I can say is that our MPs are now substance specific the safety specifications are gone organising models to increase flexibility the activities should be proportional to risks plans for studies on effectiveness and long term follow-up may be requested and may be part of the condition of the marking authorization there is a need to justify additional risk minimization activities risk minimization plan will be needed for all products and there will be a summary of the U RMP publicly available afternoon the posterization safety studies is a concept that has been introduced in the new legislation and has been expanded in the good veterans practice and this is something that is important I think because up to now there were a low level of enforcement from Ridgid or authorities to marketing authorization order so it would like first to give a legal background on these requirements in the directive 2010 84 EU 1 article has been added saying that a marketing authorization for medicinal product may be granted subject to one or more of the following conditions and if this includes to conduct pasteurization safety studies and further on it is said that a marketing authorization shall lay down deadlines for the fulfillment of this condition as necessary no perhaps more importantly that in the directive a new regulation to heart occurs have been added saying that after the granting of a marketing authorization the national competent authority may impose an obligation or the marketing authorization order to conduct a prostitue ization safety study if there are concerns about the risks of a neutralized medicine product and the imposition of such an obligation shall be duly justified notified in writing and shall include the objectives and timeframe for submission and conduct of the study so this is a rather strict level of enforcement to marketing authorization order as these imposition of poster zation safety study becomes an obligation as becomes a conditions to the marketing authorization now what's interesting is that in the directive there is also an article 107 M which says that this chapter and this is a chapter on the supervision of the posterization safety study applies to non intervention or post translational safety studies which are conducted voluntarily or person to obligations so now the directive includes a dichotomy between the studies that are imposed as an obligation and studies that are voluntarily conducted by marketing authorization orders and there are some obligations to studies that are conducted voluntarily and are a lot of publications to do that conducted has an imposition imposed by regular authorities however these also not occur saying that these supervision of post translational safety studies is without prejudice to the national and other Union requirements for answering the well-being and watch of participants so this is also an important aspect that we have to keep in mind now the directive there are a set of articles that apply only for studies that are conducted as an obligation and these articles impose and provide the proper procedure for the submission supervision and assessment of study protocols and final reports now there is also an implementing measure that has been drafted by the European Commission and this implementing measures the chapter on polarization safety studies applies only to the studies that are imposed as an obligation and they this legal text then provides the format for the study protocols and for the abstract and Finance the reports of posterization safety studies so now there will be standards mandatory format for the study protocols and and study reports I would like to stress the definition of the poster transition safety study and to mention that now this definition is made legal so it is in the legal text formerly there was a definition in the volume 9a but now there is a definition in the legislation and this list this definition as you can see is rather large it says that it is a study relating to a notarized medicine product conducted with the aim of identifying characterizing or quantifying a safety hazard but also confirming the safety profile of the medicine product or measuring the effectiveness of which Minute Man which Menem management measures so this is a very large definition of a posterization safety study and we have reflected that as possible objectives of the pass in the good vigilance practice so a possible objective that no we are consider as covered by the legislation to characterize the safety profile of a medicine to provide reassurance about the absence of a safety concern to investigate potential or identified risk to evaluate risk of a medicine product use a notarized indication by patient groups not studied in the puter ization phase to assess potential vectorization and to evaluate the effectiveness of a risk minimization activity so in the following slide I would like to explain that's not the detail the structure of the gvp chapter but more in the rationale of a number of options that have been presented in the in disruptor and explain why also it is our understanding of the different characteristics of these pedestrian safety study first of all as I told you the directive now makes a distinction between studies that have voluntarily conducted and studies that are conducted as an imposition as a propagation we consider so this study that I voluntarily initiated by mah makeover a very large range of studies because these are all the studies that are not imposed so these studies will probably cover also the studies that are read between regulators and companies when we discuss a safety issue we agree that there is a need for doing a study and the study will be included at the risk management plan so probably that these studies that are voluntarily conducted will be the majority of the studies that marketing authorization orders will will will performed so there are the the studies also that will be conducted pursuant to an obligation and as I already presented as a condition to the granting of the marketing at rejection or the directing authorization or after the granting of a marketing network the studies imposed as an obligation are a condition to the marketing authorization these studies would be justified based on benefit risk consideration and they will be very closely supervised by the pharmacovigilance risk assessment committee by NIDA prac now based on this slide I would like to make a comment and a reflection that we had when we developed a good version of practice that the legal requirements for these two types of studies voluntarily performed and from president own obligations are very different so there are a lot of obligations legal obligations for the second type of studies that are obliged however from a scientific point of view we do not consider that such differences some of the different differences and for example for the format of the protocol or for other specification are justified based on urns on days and sirens in particular many of these studies voluntarily conducted by companies will will be mentioned and will enter the risk management plan and then therefore we can have also an impact on rigor to a decision that's why in the good virgins practice we have taken the option that although legal obligations apply only to the second type or study many of the at this obligation are recommended to marketing authorization orders for the studies that I voluntarily conducted by them so what are the characteristics of this posterization safety studies first of all they can be clinical trials or non interventional studies and the mah has the responsibility to ensure that the pass is not a clinical trial if it is a clinical trial than all the legislations related to technical trials will prevail and the that legislation will apply so the module 8 of the DVP on pass mainly applies to the studies that are non interventional in the good sense practice we have provided general guidance and requirements and the guiding principle for these guidance and requirements that we have to apply and try to harmonize oh I have consistent scientific standards to increase transparency to increase immunization between the different types of studies and to ensure a minimum level of quality control so this part B of module 8 applies to all pass however as I told you the level of enforcement that we can apply to these guidance depends on the type of studies but also on different topics and that's why this module 8b is a bit complicated because we have to accommodate different bits of legislation that apply to different types of studies although we think that most of these recommendations should apply to all studies there are first of all general principles that when we when you developed protocols relevant scientific guidance should be considered investigators that will be involved in the conduct of a study have to be qualified by education training and experience and if a research contract is needed to be made with external investigator this research contract should ensure that there is continued compliance to regulatory requirements however we would like that the scientific expertise of the external investigators could be exercised throughout the conduct of the study in order to ensure high methodological standards that's why we recommend the use of the incepted of conduct as basis for the research contract study protocols so no pass can be conducted without a study protocol and the study protocols have to be transmitted to the relevant competitor it is and again there are differences between the types of study the Q P P V should be involved in order to ensure that at the national level the study will comply with the regulatory requirements we also recommend and will I will go back to this on the read registration of this protocol into a public registry of pasta to ization safety study and the substantial substantial amendments to the study protocol should also be modified and recorded an important aspect of the pass is the accurate and adequate reporting of pharmacogenes data and it includes the data relevant to the risk-benefit balance and also it there is a section on the expedited reporting of Sagres ideas and I think that for this part this is was a relief for many marketing authorization orders and investigators that for studies with secondary use of data in it is now clearly stated that there is no requirement for expedited reporting and the events and reactions should be summarized in the final study report for studies with primary use of data primary collection of data then there should be an expedited reporting where possible whether a possible relationship between an event an event and a suspected medicinal product is considered by reporter reporter or the marketing authorization order study reports progress reports may be requested before the start of the study or at any time during the study conduct because when if for that product there is a safety issue that arrived and regretted may need to know what is the progress status of studies that relate to this product and the timing may be agreed before at the state of the development of the study protocol and the agreement of the protocol the final study report has to be submitted as soon as possible after the federalization within 12 the finalization of the study and at least within 12 months and now in the gvp nodes and implementing measure there are definitions of the date of the start of the study under state the date of the end of the study and the final study report should be transmitted to competent authorities we also advise that investigators external investigators should be to publish results of a study when they delete the this the conduct of the study and something which is a recommendation we have no legal obligation for it but we would like really to have to receive the manuscripts that have been accepted before the publication it is that it happens too frequently now that we receive publications of a safety concerns the week after it has been published so it's sometimes the journalists are away before us that there is a study that has been published so we would like to have these manuscripts that have been accepted for publications within a time limit the format and the content of the study protocol since the report is defined in the implementing measure for all studies that are imposed as an obligation but there are recommended tours of all other studies we don't see why there should be a differences between studies that differs between studies that are conducted voluntarily but in put it in the risk management plan and the other studies this this format and content is a technical contribution from the AMIA to the open commission with a next committee and this is based on international guidance the space probe consort and subject is for study protocols and yet subtitle taught in family epidemiology I don't think this is this format is something new it is based on international agreed gangland what we recommend we would like to achieve a tree is the registration of studies in the EU registry of non-interventional poster tourism safety studies so this is now there is a view you may know that there is now an in separate is tree this registry will be overhauled in order to into EU registry of non-intervention or pasta tourism safety studies so it is recommended for all pass the objective of this registration is first transparency but it is also a tool for the MEA to fulfill its obligations for publish to publish the study protocols and final results of paths that have been imposed concerning centralized products it is also a very important tool for exchanging information and it will also help minimize administrative procedures and duplication of work between different national company charities or would like to study the same types of safety issues there are obligations for study that I imposes obligations for traceability and documentation of trained to the data there is a possibility to in inspect an audit analytical data set and statistical programs used to generate the result and also mah suit I'm sure that the external investigators are qualified by education training or experience to perform the task and there should be documentation of this qualification and my final slide I think it's that there are also specifications and regarding data protection the mah certain sure that also the information is handled and stored in such a way that it can be accurately reported interpreted and verify while the confidentiality of the disability remains protected this in something that is that we considered very important to through to our physics and I think this is my last like yes thank you