A Stitch in Time. Understanding and Preparing for the IDMP from a Strategic Level REPORT

Transcription

1 A Stitch in Time Understanding and Preparing for the IDMP from a Strategic Level REPORT Outsourcing and Consulting Services for Life Sciences

2 Table of Contents Regulatory Deadline: Driven by EU Legislation...2 Top Level: How IDMP Differs from XEVMPD...3 Important Set of Standards with Significant Implications for Industry...4 A Closer Look at the Standards...5 Relationship between XEVMPD and IDMP...10 Implementation Plans and Needs...12 Overall Plans and Timelines...14 Moving Ahead for Industry...14 References...15 i

3 As the Identification of Medicinal s (IDMP) was coming into clearer focus, Life Group worked with Andrew Marr as part of PLG Evolve, Life Group s thought leadership programme, to develop and publish a formative paper on this important issue. The regulators have made clear their intention to meet the 1 July 2016 legislative deadline for implementation of IDMP. An expansive and widely encompassing set of standards, the IDMP is a significant undertaking for all parties the authorities, committees, and experts involved in its development and implementation and for the organisations that will be affected by its introduction namely, life sciences companies. IDMP is expected to be used for a wide range of regulatory purposes and beyond, making it a far more comprehensive set of standards than the extended EudraVigilance Medicinal Dictionary (XEVMPD), which it will replace. For companies, the ability to control their data in order to respond to any and all requirements will be a most important aspect. They will need to know where to find their data whether regulatory, pharmacovigilance, quality, or manufacturing and how best to assemble it. To do so, companies need to ensure their regulatory information management systems (RIMs) are able to manage all information related to their product portfolios on a global basis. Taking a strategic approach to the IDMP requires companies to have their own internal processes and RIM strategies in place and that they be in a position to quickly react to content in the implementation guides as the guides become available; that availability is expected to start in mid IDMP is a significant undertaking, but it also presents opportunities in terms of how companies manage and share data and particularly as a way to support master data management initiatives. This paper explores what IDMP is, its broader potential across life sciences and health care, and the implications for companies in the lead-up to implementation. Erick Gaussens, Chief Scientific Officer Life Group 1

4 Regulatory Deadline: Driven by EU Legislation The implementation of IDMP is being driven by legislation in the European Union (EU). The Commission Implementing Regulation of 19 June stipulates that the International Organization for Standardization (ISO) standard for IDMP will be used for the provision of medicinal product information, that the implementation date is 1 July 2016, and that IDMP will also be used in the context of submission of Individual Case Safety Reports, a new version of which, based on the ISO standard, 2 is to be implemented at the same time. Thus, XEVMPD will be replaced by IDMP, which has a significantly wider scope. The European regulators have made clear their intention that IDMP will be used in support of a broad range of regulatory requirements beyond capturing the data associated with initial registrations and life-cycle submissions in support of pharmacovigilance. With that in mind, the European Medicines Agency is currently working with its experts, committees, and the wider regulatory network of national competent authorities to define additional requirements for provision of data that will support the following areas. Clinical trials particularly in the context of the new clinical trials regulation Scientific advice Paediatric usage Inspections and quality Assessment of the potential use of IDMP for clinical trials and scientific advice demonstrates the desire to capture information early in a medicine s life cycle. That would facilitate continuity of tracking once the product is authorised for marketing. Potential use for inspections and quality could significantly expand the applicability of IDMP because use in those areas does not necessarily involve dossier content. For example, the manufacturer of excipients is not in the dossier but should be known to the manufacturing company. Because the inspectorate and regulators require this data to be provided centrally, the data s availability could facilitate management of issues of potential contamination, a problem that has arisen in the past. The European Medicines Agency plans to report on its assessment later in 2014 and to propose the use cases and required data once IDMP has been implemented. The use of IDMP has potentially greater reach beyond regulatory processes. Projects are being initiated by the European Commission 3 to support provision of individual-patient health-care records between countries and to support the filling of electronic prescriptions in another country. It is highly likely that IDMP will play a significant role in those endeavours. 2

5 The IDMP standards were published in October 2012, but there is much to do before they can be implemented. Implementation guides need to be written, agreed on, and published; processes defined and implemented; vocabularies developed, published, and readied for maintenance; and systems for data management and submission delivery and receipt developed, tested, and implemented. The regulators are working diligently towards the deadline and are committed to meeting it, but with so much to accomplish and so many earlier deadlines to be met first, achieving the goal of 1 July 2016 implementation will be tight. There are many lessons to be learned from XEVMPD, the most notable of them that time will be needed to pull good data together and manage it well. Two years is not a long time to prepare, considering the complexity and breadth of the data involved. Unlike with XEVMPD, when timelines allowed companies to adopt only tactical solutions, for IDMP strategic approaches should be considered; and companies are advised to prepare for that now and not be forced into making a knee-jerk reaction in the final few months before implementation. Two significant lessons to be learned from XEVMPD are that companies need to be in control of their data and that to be able to provide quality data there must be good guidance that companies can interpret in only one way. For many companies, that was not achieved at least in the early stages of XEVMPD, when their RIMs and the data held within them were not up to the required breadth, depth, and quality. At many companies, that issue is in the process of being rectified, but IDMP will put a further strain on their ability to manage data. IDMP also has far wider geographic scope than the XEVMPD had, because it is not confined to Europe. Other regulators beyond those in the EU will be implementing IDMP; however, they do not have the legislative deadlines to target. The US Food and Drug Administration (FDA), in particular, is putting significant effort into moving the implementation support activities along both within and outside ISO. Top Level: How IDMP Differs from XEVMPD IDMP is a set of global standards, developed in collaboration between regulators, industry, and health informatics professions. Although the initial purpose was the identification of substances and medicines for pharmacovigilance purposes, during the process of development of the standards the scope became significantly broader, encompassing many other regulatory-use cases. The result is something much broader and deeper than XEVMPD. Although the initial purpose was the identification of substances and medicines for pharmacovigilance purposes, during the Because the development of the standards took place in collaboration with health process of development informatics standards organisations, IDMP is not an isolated set of standards the of the standards the scope way XEVMPD is. IDMP is better designed than XEVMPD and will correct many of became significantly the problems seen with XEVMPD and for which inelegant workarounds have been required, such as handling multiple languages in a country and supporting the broader, encompassing identification of multiple presentations within the same authorisation. many other regulatoryuse cases. The data required for XEVMPD was predominantly already held by regulatory affairs, although for the majority of companies, some additional data had to be collected from within regulatory affairs. In addition, a typically limited amount of information came from pharmacovigilance and drug safety. IDMP pushes further into pharmacovigilance, including the use of IDMP data in Individual Case Safety Reports. It also goes further than XEVMPD because it encompasses aspects of manufacturing, technical operations, and chemistry, manufacturing, and control regulatory, including details of the packaged medicinal product (manufactured product), details of the pack, its components, its ingredients (substances, specified substances, process steps, grade), manufacturing sites, manufacturing operations authorised at specific sites, details of the authorising regulator, and much more coding of data in the summary of product characteristics (SmPC). There is no data that a company should not have, but the main challenges are to identify where the data is to be found and how it should be collated. 3

6 Providing IDMP data for the European Medicines Agency will support master data management for the EU regulatory network. Master data management involves the establishment of a single, authoritative source for specific pieces of information. The information will not be data solely for the agency but will be used to facilitate Pan-European activities and data sharing. The agency is creating master data sets for the following, which will feed a variety of information systems, as follows. Substance Organisation Referentials (other vocabularies) Important Set of Standards with Significant Implications for Industry IDMP is a set of fi ve interrelated standards, as defi ned in table 1. Table 1. List of IDMP standards ISO Number ISO 11615:2012 ISO 11616:2012 ISO 11238:2012 ISO 11239:2012 ISO 11240:2012 Title Health informatics Identification of medicinal products: Data elements and structures for the unique identification and exchange of regulated medicinal product information Health informatics Identification of medicinal products: Data elements and structures for the unique identification and exchange of regulated pharmaceutical product information Health informatics Identification of medicinal products: Data elements and structures for the unique identification and exchange of regulated information on substances Health informatics Identification of medicinal products: Data elements and structures for the unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration, and packaging Health informatics Identification of medicinal products: Data elements and structures for the unique identification and exchange of units of measurement The standards describe the product as authorised and on the market (the medicinal product), and they support a general concept regarding the administered product (the pharmaceutical product); the substances that are included in the medicinal product and those that are in contact with it; details about further classification of substances to identify specific physical forms, specific manufacturers, processes, and grades of materials (specified substances); and a series of controlled vocabularies to be used in describing products. Collation and provision of IDMP data will have significant ramifications for industry but also potential opportunities for the ways companies manage and share data. Overall, IDMP is not data that sits solely in regulatory affairs, and significant parts of it are or should be corporate data. Essentially there is the potential that IDMP can drive or support master data management initiatives in industry as well as at the European Medicines Agency. The need to address provision of additional information can be a driver for rationalising the ways companies manage their own data whereby they establish a single authoritative source that is aligned with the ISO standards rather than create yet another instance of data that might have to be manipulated and then maintained independently. 4

7 Challenges for most companies will be: Locating an appropriate source of the relevant data Ensuring that the data aligns with the granularity, vocabularies, and data types of IDMP Establishing a mechanism to maintain the data Ensuring consistency of the data to be submitted with that which may be identified during pharmacovigilance or good-manufacturing-practice inspections It will be desirable to establish a single, authoritative source for each data point, but that may not be achievable, particularly if an IDMP project is not initiated in time. With implementation scheduled for 1 July 2016 and given the amount of analysis and preparation needed, it is advisable to start preparing now, even if we don t know precisely what the European Medicines Agency will want until the implementation guides become available, which is not expected to start happening until summer It will take time to determine where and how data is to be sourced and to ensure that efficient processes and technology are in place to support data collection. If an IDMP project is initiated too late, there will be only limited opportunities to implement strategic solutions, with time only for tactical approaches to be used. Just remember the problems that were encountered in responding to the XEVMPD requirements, but multiply them several times for the equivalent of response to IDMP. The focus so far has been on the requirements for authorised products, but the standards also cover investigation of medicinal products. Regulators see the importance of continuity of information throughout the life cycle of a medicine, from clinical trials through marketing and, eventually, discontinuation. However, at this stage there are neither clear plans for development of implementation guidance nor intended implementation dates for the use of IDMP in support of investigational products. A Closer Look at the Standards Medicinal Medicinal Identifier (MPID) (ISO 11615) This standard defines the data that describes a medicinal product. In this context, a medicinal product is equivalent to a marketing authorisation whether it is for a one-pack configuration (e.g., as in France) or for manypack configurations (e.g., as in the United Kingdom). Although the medicinal product is equivalent to the authorised product in XEVMPD, the data described is far more extensive. The assignment of the MPID will be managed regionally by the regulator. The MPID will be in an identifier format different from the product EV code in XEVMPD. It is crucial to understand the standard for the medicinal product because that standard will define the majority of the information that will have to be submitted to any regulator. At its simplest, a medicinal product, as defined by IDMP, can be regarded as a replacement for the authorised medicinal product (AMP) in XEVMPD. All of the information contained in the set of data for an AMP can be accommodated in the medicinal product, but there is also significantly more data defined within the medicinal product. In the MPID model are many mandatory elements that are beyond the scope of the AMP. However, not all elements are mandatory, because many are technically optional meaning, the model does not require them to be provided; but in the EU, it is anticipated that many of these will be required by business rules. At present there is no clarity regarding which optional elements will be required, because the regional implementation guide is not yet available. In the latter part of 2014, based on analysis under way, the European Medicines Agency and the national competent authorities should be proposing the mandatory fields in support of particular business processes. The FDA s position, too, is unclear, but a likely approach, over time, might be that all data within the scope of IDMP, if already included 5

8 in a New Drug Application or Biologics License Application, will transition from being included in the dossier in an unstructured way to being provided in a structured message for IDMP. That way, the FDA would populate databases with information provided rather than having to hunt through dossiers to find related data for different products. Figure 1. High-level model of the medicinal product Version Medicinal Name Clinical Particulars Figure 1 shows the high-level sections of the medicinal product. Main points regarding each of those sections are further described after the figure. Manufacturer/ Establishment (Organisation) Medicinal Pharmaceutical Medicinal, Medicinal Name, and Version Each medicinal product will have an identifier: the medicinal product identifier, or MPID. The MPID will be set at the level of the authorisation. It will be a code in addition to that of the Marketing Authorisation Packaged Medicinal authorisation number and will also be different from the product EV code in XEVMPD. More product name parts will be supported, covering such parts as flavours (e.g., orange flavour), intended use (e.g., hay fever relief), and target population (e.g., children). IDMP will address those needs in a well-considered way, unlike in XEVMPD, wherein the June 2014 revised guidance 4 makes it clear that in XEVMPD, several of these name parts are to be included in a single field. In IDMP, they are separated into individual fields. The language for the name will also be defined and will resolve the problem seen in XEVMPD in countries like Belgium, where different languages have required different EV codes. Regulated documents will still need to be supplied, but each region will have to define which specific documents it requires. It may continue to be the SmPC only in the EU, or the requirements could change. In IDMP, a stricter version control will be applied compared with XEVMPD, with any change made creating a new version, either major or minor depending on business rules. Marketing Authorisation In principle, the information to be provided is similar to the data supplied in XEVMPD such as marketing authorisation number, procedure type, procedure number, and marketing authorisation holder (MAH) but there are also certain significant differences to address items that aren t dealt with. Additional information defined covers the legal status of supply (e.g., prescription or nonprescription) as well as information about the marketing application, including number and date; information about schedules for the Periodic Safety Update Report; and information about the marketing status of the product (i.e., marketing start and stop dates). The marketing status highlights one of the current issues regarding the true requirement for certain fields. In this case, the fields are technically optional in the model the reason being that at the beginning of the life of a medicinal product, it can be authorised but not yet marketed; and so the record has to be able to exist without a marketing status. The European Medicines Agency may implement a business rule that once a medicinal product is marketed, the marketing start date must be provided, thereby making this field mandatory. Those are the types of issues being considered by the agency and the EU regulatory network; the issues will be covered in the regional guidance. Until that stage, we are left with uncertainty. The way the MAH, locations, contact details, and so forth are to be provided will be different from the way they re provided in XEVMPD. The structure is quite different, but remapping of existing information may be possible. It will 6

9 also be necessary to define the medicines regulatory authority that has authorised the medicinal product. Because it is intended that regulators share parts of the MPID data to support pharmacovigilance activities, it is considered important to define which regulator has authorised the product. Manufacturer/Establishment (Organisation) This is information not currently included with XEVMPD, but some is already in the regulatory dossier usually in the application form and Modules 2 and 3. It defines the manufacturer(s), the contact details, the operations performed at the defined locations, and the medicines regulatory authority that has granted the authorisation to conduct the manufacturing operation. The information about the agency may not be in the dossier, but it will be known within the organisation, although it may not be readily available in a database and so may need to be collated. Packaged Medicinal In XEVMPD, the product is defined as an administrable product. This is also included in IDMP, but in addition, the concept of the packaged medicinal product has been added. It defines each pack size authorised, and an identifier will be assigned to each package configuration. This move will resolve a major issue in XEVMPD, where there has been flexibility to define the EV code at either the authorisation level or individual pack sizes within that authorisation. IDMP separates the two. The European Medicines Agency has already indicated in several announcements during 2014 that it will be requiring records at this level once IDMP is implemented in The standard for packaged medicinal product supports the ability to describe the product in great detail. The description defines the outer packaging (e.g., carton), intermediate packaging (e.g., cartons within cartons), containers (e.g., blister packs, vials), and the manufactured product (e.g., tablet, solution) and its ingredients (substances and specified substances). It can define the components of a container (e.g., bug, cap) and any device (e.g., administration device) that is included in the pack. It defines the product s shelf life and storage conditions, materials (types of glass, plastics, etc.), physical characteristics (e.g., size, colour, shape, image), and more. For products like powders and solutions for suspension for injection, each vial will be described individually, with its respective ingredients. The administrable dosage form and its ingredients are described in the section Pharmaceutical. A significant proportion of this information is likely to be required because the model defines it as mandatory, but some is defined as optional. Again, the EU guidance will have to define what is required and under which circumstances. The inclusion of Inspections and Quality as part of the European Medicines Agency s review of what information may be required raises the potential that more optional information becomes mandatory. Some of the information is likely to be available in the dossier, but some may need to come from the manufacturing organisation. Pharmaceutical This section approximates to the product formulation as currently defined in XEVMPD namely, the administrable dosage form. In a lot of cases, the administrable dosage form is the same as the manufactured dosage form (e.g., tablet), so the information will be repeated. However, in cases in which the manufactured dosage form is different from the administrable dosage form (e.g., powder and solution for injection versus solution for injection), a different term will be defined. The route of administration is provided along with the set of pharmaceutical product identifiers (PhPIDs) that are assigned to this pharmaceutical product. (Described in greater detail in the section, Pharmaceutical Identifier). 7

10 Clinical Particulars Figure 2. Intermediate-level model of clinical particulars In XEVMPD, the only clinical particulars defined are the indications, coded in the Medical Dictionary for Regulatory Activities. A criticism that can be made of this is that the coding can be imprecise and not provide any differentiation between how products are really used. The approach in IDMP is to provide the potential to capture a far wider set of data, associated not only with the indication but also with contraindications, including populations in which the product is approved for use and other therapies that may further classify use. Furthermore, undesirable effects are to be described along with any interactions and the interactant concerned (figure 2). This provides additional support for safety analyses. The European Medicines Agency is already requiring that up-to-date SmPCs be provided and that when these sections change, new versions are also provided. Provision as structured data will enhance the ability to compare across products, indications, contraindications, and so on. Therapeutic Indications Medicinal Clinical Particulars Undesirable Effects Population Specfics Other Therapy Specifics Interactions Contraindications Interactant Some but not all of this information is defined as required within the ISO model, and so, regional guidance will be needed in order to understand the regulator s intent. However, the potential impact could be significant. Far more coding could be required, but the resulting characterisation of the prescribing information would be far more descriptive and useful than the current coding of indication alone. In terms of therapeutic indications, together with population specifics and other therapy specifics, the following examples demonstrate the coverage of these parts of the standard. Indication text: As per the SmPC Indication as disease/symptom/procedure: Treatment of primary hypertension (as currently in XEVMPD) Disease status: Treatment of chronic active liver disease Comorbidity: Treatment of pneumocystitis pneumonia in AIDS Intended effect: Passive immunisation against rabies infection Timing/duration: Prevention of atherothrombotic events in patients with ischaemic stroke (from 7 days until 6 months) Age: Indicated in paediatric patients Age range: Adults older than 35 years with primary hyperlipidaemia Gender: For the treatment of men with prostate cancer 8

11 Race: e.g., Caucasian, Afro-Caribbean, Hispanic (although this is rarely applicable to indications but often applicable to contraindications) Health status: Can be used during lactation Therapy relationship: Following prior treatment with proton pump inhibitors Medication: Prevention of atherothrombotic events in combination with acetylsalicylic acid The SmPC is a complex document, and coding of the clinical particulars has the potential to involve a significant amount of work. For many products, the SmPC changes on a frequent basis as the use of the medicine grows, new indications get defined, undesirable effects and contraindications get identified, and so forth; and so the maintenance of this information will also be a significant activity. Ingredients and Substances For both the packaged medicinal product and the pharmaceutical product, each ingredient will have to be identified and its role defined. This task is likely to go beyond just defining an ingredient as, say, active ingredient, or adjuvant, or excipient. For excipients, the purpose in the product is likely to need definition (e.g., preservative, flavouring, mechanical ingredient). Depending on what rules are to be defined in the implementation guidance, this could be either as general substance IDs or as more-precise specified substance IDs. As mentioned earlier, the specified substance could define the physical characteristics (e.g., crystalline or amorphous), the general manufacturing method (e.g., synthetic, extractive, recombinant), the specific manufacturer (e.g., Manufacturer A or Manufacturer B), and/or the grade of material used (e.g., EP or USP). One of the advantages of defining the active ingredient and its strength by use of the IDMP model is that the IDMP model makes clear what substance is being defined and what its strength is. In IDMP, it is possible to define not only the substance and its strength but also the reference substance and the reference strength. In XEVMPD, it is possible to define only one, which causes confusion as to whether to define the base, salt, or active moiety and then to have the correct strength according to the SmPC. Clearer guidance has been provided in more-recent XEVMPD guidance, but because of XEVMPD s design, there are significant constraints regarding what can be achieved, and lack of clarity may well persist. In IDMP, however when applicable there may be a requirement to define both: for example, the salt and its strength and the base and its strength. The final rules are yet to be defined, but the potential is stated. The substance IDs will not be the same codes as in XEVMPD but may well be the Unique Ingredient Identifier (UNII) codes the FDA currently uses, but that is yet to be confirmed. The European Medicines Agency is currently assessing (1) whether to use the FDA s new Substance Registration System (Global Ingredient Archival System, or GInAS), which will be compliant with the ISO standard for substances, and (2) whether the FDA s UNII codes should be the European codes as well. A decision is expected later in From an industry standpoint, it would be much simpler if the agency committed to a global process and a global identifier; otherwise, there will have to be parallel activities on both sides of the Atlantic. However, the FDA s substance registry is not comprehensive, and although most chemical and biological active ingredients and excipients are included, the registry does not yet cover such substances as herbals and homeopathics, which are required to be included for XEVMPD. Nor does it contain any specified substances, which are likely to play significant roles for many types of product in describing a product s constituent ingredients. It is clear that a great amount of work will be required to create a globally recognised, controlled vocabulary for substances one that holds all of the data defined in the standard for substances (ISO 11238). If the Structured Substance Information had progressed in XEVMPD, it would have been the responsibility of all MAHs to provide detailed information for every substance they used in their products. That should not be the case with IDMP, and only a single record will be created. Many substances may already be defined adequately in the databases of the FDA, the Medicines Evaluation Board, and Germany s Federal Institute for Drugs and Medical Devices; and it is intended that a global pool of substance data be created from existing sources although the European Medicines Agency has yet to 9

12 commit to this and will not do so until its analysis is complete. That s why it s not yet clear where responsibility would lie for substances not included in any database or where data needs to be augmented to bring it up to the required standard. Will the burden fall on industry? Or will it be the responsibility of one or more regulators? Relationship between XEVMPD and IDMP As discussed in this paper, the scope of data covered by IDMP is significantly larger than that covered by XEVMPD. Figure 3 visualises the degree to which information in IDMP is either essentially the same as XEVMPD, or is similar but may have some more fields, or is completely new data not previously covered at all in XEVMPD. Even when the data are the same or similar, there are the possibilities that they will be at different levels of granularity or that a different controlled vocabulary will have to be used. There is no doubt that some data can be mapped easily between the two, but there is still much that will require some intervention to realign. As for the new information, sources for it would have to be identified within an organisation. Figure 3. Scope of IDMP data compared with XEVMPD data Country/ Language Medicinal Classification Undesirable Effects Interactions Interactant SAME Regulated Document Version Medicinal Name Clinical Particulars Contraindications Therapeutic Indication Population Specifics Other Therapy Specifics Manufacturing Operation Medicines Regulatory Agency SAME Marketing Authorisation Holder Manufacturer/ Establishment (Organisation) Marketing Authorisation Medicinal Packaged Medicinal Pharmaceutical PhPID Set Pharmaceutical Characteristics Route of Administration SAME Ingredients SAME Substance Specified Substance SAME Strength Reference Strength SAME Marketing Status Batch Identifier Package Item (Container) Periodic Safety Update Report Submission Marketing Authorisation Procedure Shelf Life/ Storage Data Carrier Identifier Manufactured Item Other Characteristics Marketing Authorisation Application Package (Component) Device Physical Characteristics Device Nomencalture Device Batch Identification 10

13 Pharmaceutical Identifier (ISO 11616): This standard defines the concept of a pharmaceutical product an issue not addressed in XEVMPD. The same PhPIDs will be assigned to all medicinal products that have the same characteristics including substance, dosage form, and strength regardless of the country they were authorised in (figure 4). The PhPID is key to improving pharmacovigilance by enabling greater confidence in data that comes from other regulators. This can then be used to create larger sets of product data to be used for signal detection. It is yet to be decided whether the PhPID or, more correctly, a set of PhPIDs will be assigned by regulators or MAHs, because it is to be created via an algorithm based on component identifiers. The identifier assigned will be the same globally because it will be based on the substance, strength, and dosage form, all of which should be globally applicable identifiers subject to the European Medicines Agency s agreement on the substance ID. Figure 4. Relationship between MPID and PhPID Pharmaceutical Common PhPID Set Japan Branded A MPID1 USA Branded B MPID2 France Branded Generic C MPID3 France Generic D MPID4 Germany Branded Generic E MPID5 Germany Branded Generic F MPID6 Canada Branded Generic G MPID7 Substance Identifier and Specified Substance Identifiers, ISO This standard describes the data for uniquely defining substances such as active ingredients, adjuvants, and excipients but also packaging materials, even though likely to be only those that are in contact with the drug. The standard also defines data that can further describe substances in a variety of different ways as specified substances. Specified substances can define substances from different manufacturers, with different grades, and can support high-level and detailed manufacturing-process descriptions as well as multiconstituent substances such as colourants, flavours, and culture media. The Structured Substance Information, initially defined as part of XEVMPD but later withdrawn, was based on this standard. The identifiers will be assigned globally by regulators subject to the European Medicines Agency s agreement. It is clear that to be able to classify some types of substances adequately and so differentiate between them, the use of the specified substances will be important. For many herbals, polymers, and advanced therapy products, the detail to be found in the specified substances part of the standard will be necessary in order to uniquely differentiate between substances that at the substance level are essentially similar but may have very different factors that could affect safety for example, solvents used for extraction. Simple chemical/structural definition is insufficient to define and differentiate such substances. Many challenges lie ahead before achievement of implementation of the substance standard on a global scale, but they are not insurmountable. 11

14 Control Vocabularies, ISO This standard defines how controlled vocabularies are to be created to cover routes of administration, pharmaceutical dosage forms, units of presentation, and packaging. These will be global vocabularies, and existing regional vocabularies will have to be mapped to them. There may be differences between the vocabularies used for XEVMPD and for IDMP, but there is the potential that the European Directorate for the Quality of Medicines & HealthCare s (EDQM s) standard terms used in XEVMPD will become the terms for IDMP. That decision has yet to be made. Packaging will be a new controlled vocabulary, because nothing similar exists at present. Units of Measurement, ISO This standard stipulates that an existing standard for units of measurement the Unified Code for Units of Measure (UCUM) standard will be used to define the strength of medicinal products. This standard is already used in XEVMPD, although some terms used provisionally in XEVMPD need to be included formally in the UCUM standard. Implementation Plans and Needs The implementation date for IDMP in the EU has been defined as 1 July At present, it has not been stated what that date refers to precisely. In July 2011, when the European Medicines Agency announced the requirements for XEVMPD, reference was made to implementation of IDMP (at that stage, 1 January 2015) but that it would be a transitional process taking place over a 12-month period, beginning with new products submitted in IDMP format, changes to existing product records necessitating conversion to IDMP, and any remaining records migrated at the end of the 12 months. There is no guarantee that this will be the same from July 2016, but a transition period is expected. Implementation by the FDA is not defined by legislation, but the agency plans to implement at an appropriate point, with evolution of its Structured Labeling requirements. The FDA s To meet that deadline much needs to occur, but there is significant commitment plans would need to be from other regulators and the pertinent ISO technical committee to facilitate formally announced for achievement of the date. comment in the Federal Register. Implementation by the FDA is not defined by legislation, but the agency plans to implement at an appropriate point, with evolution of its Structured Labeling (SPL) requirements. The FDA s plans would need to be formally announced for comment in the Federal Register. However, the FDA s long-term goal is for as much data as possible to be structured within IDMP rather than in an unstructured manner in the submission dossier. The Swiss, Canadian, and Japanese regulators are also contributing to the implementation activities. Beyond the International Conference on Harmonisation (ICH) group of countries, Australia, Russia, and Iran have nominated or will be nominating experts for development of the implementation guide for substances, thereby suggesting widening interest in the standards as they are progressed. It is not possible to take the standards and implement them. Several supportive items, described as follows, are required, and either (1) these are in the process of being progressed or (2) there are dependencies, which means they have not yet started. Common implementation (ISO) guidance: This guidance is designed to provide a common interpretation of the IDMP standards so that all fields will be used similarly whenever implemented. Although initiated within ICH, this activity has passed to ISO Technical Committee 215, Working Group 6, which is the group that developed the standards. Work on the implementation guide for substances (ISO 11238) has been initiated and the first ballot 12

15 undertaken, which elicited from industry, regulators, and software vendors a large number of comments that need to be addressed. In addition, the work being undertaken by several regulators in the GInAS project has identified a number of further implementation needs. A tentative date for release of the ISO implementation guide for substances is July Three other implementation guides will be needed: one each for the medicinal product (ISO 11615), the pharmaceutical product (ISO 11616), and the set of vocabularies (ISO 11239). Work has not started on these, but the first ballot is expected by the end of 2014, with publication provisionally targeting December There are no plans to produce an implementation guide for the units of measurement standard (ISO 11240), because this is an existing standard. Messages: As with XEVMPD, in which the extended EudraVigilance Report Message is used as a message from the MAH to the European Medicines Agency, so messages are needed to be able to send and receive acknowledgements between the MAH and regulators, potentially between regulators, and between regulators and the public. These will be messages that apply the Health Level 7 (HL7) standard, probably as part of an extension to the SPL standard already used by the FDA. Proposals to extend the SPL scope will be made to the appropriate HL7 committee before the end of Regional implementation guidance: The common implementation guidance does not state specifically what each individual region requires, and so for each implementation, it will be necessary to define some specific, augmented regional implementation guidance that will identify, for example, exactly what information will be required, under which circumstances, how it will be submitted, and so on just as the XEVMPD guidance does now. Each region may choose to require different data (although there will be a common, core set of data that all will require), so implementation in the EU could be significantly different from implementation in the United States. The European Medicines Agency has determined that only two regional guides will be required: one for the medicinal product and one for the substances. Because the pharmaceutical product and the vocabularies for dosage forms will have the same values globally, there will be no need for regional guidance. To publish the regional guidance in time for 1 July 2016, it will be necessary to develop these guides in parallel with the ISO guides. Initial plans stipulate that a good draft of the ISO guide will be used as the basis on which the EU guides get drafted. Drafts will have to be circulated for comment, and it may be necessary to treat a final draft as the basis for implementation. The earliest date on which the EU substance implementation guide would be published is July 2015; the earliest for the medicinal product guide would be December 2015, only seven months before the implementation date (table 2). Maintenance organisations: Organisations have to be identified for the creation and maintenance of controlled vocabularies and identifiers. It will involve the regulators, which will be issuing regionally defined controlled vocabularies and identifiers but which are working collectively where the controlled vocabularies and identifiers are to be global. Certain specific standards development organisations and other institutes, such as EDQM, will have to be involved as well. The regulators are continuing to work in a group known as IDMP External Group on collective activities in support of implementation. However, each regulator will have to make decisions about who will act as its maintenance organisations. It is hoped that regulators will each select the same maintenance organisation, but it is possible that they may select different ones. For the success of the implementation, it is essential that all of the organisations involved work to defined processes and quality standards. To achieve that goal, ISO is developing the Core Principles for Maintenance of Identifiers and Terms, which will set the quality standards expected. 13

16 Overall Plans and Timelines The European Medicines Agency is in the process of developing an implementation road map for IDMP. A precursor to that process has been ongoing work with the EU regulatory network to determine which fields will be required and for what purpose. It is likely to be late-third-quarter or early-fourth-quarter 2014 before the agency makes a proposal to industry via the Article 57 Implementation Working Group. Much negotiation may be necessary before a firm road map is agreed on. As mentioned previously, development of the ISO implementation guides has started for one standard but needs to be started for the other three standards. Additionally, two EU guides need to be produced. Table 2 outlines the potential dates, if indeed the agency runs development of the EU guide in parallel. The most crucial implementation required is for the medicinal product, because that implementation will cover the vast majority of data needing submission. However, this is on the tightest timeline, and it is necessary to provide as firm a foundation as possible for implementation planning and as soon as possible. Good drafts made available throughout 2015 will prove very beneficial. Table 2 identifies the anticipated implementation guides and the target or potential publication dates. Table 2. IDMP implementation guides IDMP Standard ISO 11238: Substances ISO 11239: Vocabularies ISO implementation guide (target publication date) Yes (June 2015) Yes Regional implementation guide (potential earliest publication date) Yes (July 2015) No (December 2015) ISO 11240: Units of Measurement No No ISO 11616: Pharmaceutical Yes No ISO 11615: Medicinal (December 2015) Yes (December 2015) Yes (December 2015) Moving Ahead for Industry Several potential options are available to industry for planning to move ahead with IDMP. They can be summarised as follows. Ignore the standards and the implementation for now, bearing in mind that they won t go away. At some point, they ll need to be addressed to maintain compliance with regulations. Wait until the guides have been released, though it may prove too late to approach the solutions in a strategic manner. Potential benefits will be missed, and companies will be left with just the cost of compliance. Start now, based on what is known and what can be predicted, to assess, monitor, and plan. Doing so offers the opportunity to look for internal benefits and efficiencies such as applying the IDMP standards internally and establishing a single, authoritative source of data for multiple purposes. However, this would require the application of significant resources and at a time when much work is required for the updating of XEVMPD data and the implementation of maintenance processes. It may be difficult to progress both at once. 14

17 The following points may be considered industry current best practice to move ahead with IDMP projects. Recognise the need to address IDMP because typically, regulatory affairs and/or regulatory information technology is pivotal in initiating it. Gain sufficient understanding of the standards (to a level beyond what this paper provides) by at least a small group to determine the implications of IDMP implementation for the company. Obtain sufficient sponsorship to convene a group that together will develop a vision and strategy for IDMP assessment and implementation (often called a preproject). Develop a vision and strategy and seek endorsement from an executive committee with a broad base of coverage because management of the data is or should be considered a corporate responsibility. Establish sponsorship for the main project, typically regulatory led but with adequate corporate-level commitment to provide the necessary resources. Broaden the base of understanding of the standards within the organisation. Conduct an analysis of where the data resides or doesn t in the company and how it can be brought together, considering the challenges and opportunities that that may pose. Establish the strategic approach to data management in the forms of: Regulatory compliance only for Europe Regulatory compliance for global markets Compliance in the context of master data management Establish and initiate implementation plans. Plan to fine-tune strategy as guidance becomes available. Influence guidance by providing comments based on detailed assessment of the implications to the company not just on theory. Influence vendors of RIM systems in the development of their own tools and strategies. In essence, this process can be summed up as, plan now so that the company can be in a position to act. The process should not be limited to companies that have their own RIM systems at present. Even though data entry via an updated European Medicines Agency Web-based tool will no doubt remain possible, the anticipated scope of the required data is likely to be on a scale that will stretch many companies abilities to effectively manage their data via, for example, spreadsheets. Consideration should be given to the tools necessary to manage the information internally as well as to deliver it to regulators. IDMP will be upon us soon. The more time a company takes to prepare and the sooner those preparations start, the better position that company will be in to respond. References 1. Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive. 2. ISO/HL :2011 Health informatics -- Individual case safety reports (ICSRs) in pharmacovigilance -- Part 2: Human pharmaceutical reporting requirements for ICSR; catalogue_detail.htm?csnumber= Personalising Health and Care: ehealth interoperability; desktop/en/opportunities/h2020/topics/2257-phc html. 4. Detailed guidance on the electronic submission of information on medicinal products for human use by marketing authorisation holders to the European Medicines Agency in accordance with Article 57(2), second subparagraph of Regulation (EC) No. 726/2004: Chapter 3.II: Extended EudraVigilance product report message (XEVPRM) user guidance; WC pdf. 15

18 Life Group is a trusted partner that helps clients stay ahead of the changing R&D landscape. We provide support across all stages of the product life cycle and have experience in working with companies in all segments of the life sciences industry. With an established presence in five European countries, extensive capabilities in key markets, and more than two decades of serving the industry, Life Group has a solid platform from which to provide clients a range of services, consulting, and outsourcing solutions. We empower clients to focus on innovation and business growth strategies and to make strong, informed decisions every step of the way. What s more, we wrap it all up with partnership flexibility, for a truly custom experience that helps clients scale their initiatives cost-effectively. By leveraging the power of deep domain expertise, relationships, collaboration, and a flexible delivery framework, Life Group delivers exceptional service to clients. Our goal is to develop long-term relationships by being responsive and relevant and by consistently delivering value. We cultivate a trusting, consultative environment and are positioned to operate as an extension of clients businesses, with a shared interest in their long-term success. Life Group Head Office 24 rue des Moulineaux, Suresnes, France Tel info@productlife-group.com BELGIUM FRANCE GERMANY SWITZERLAND UNITED KINGDOM Outsourcing and Consulting Services for Life Sciences