EMA’s Union Product Database implementation guide updated (again!)

Action required: Union Product Database implementation guide is available for consultation until 21/March/2021.

Today, I shall look at three of the many changes proposed.

The first important update.

Under the New Veterinary Regulations (NVR) EU 2019/6, the European Medicines Agency (EMA) shall establish and maintain a Union Product Database (UPD). In previous blogs we looked at some of the new requirements such as UPD access policies and what it might mean for Marketing Authorisation Holders (MAHs) to deliver additional information on veterinary medicinal products. Now on 21/January/2021 the EMA released a draft implementation guide on the UPD for public consultation and one of the main areas for MAHs to consider is the implementation timelines.

Source: EMA Veterinary Regulation Highlights, Issue 3, January 2021

These timelines define when MAHs and competent authorities have to manage veterinary medicinal product information in the UPD. And these timelines are tight.

The Veterinary EU Implementation Guide for the Union Product Database

The second important update.

The EMA provided the UPD implementation guide (EMA/536780/2020, 21/January/2021) to support MAHs as well as competent authorities who are submitting veterinary medicinal product data into the UPD. The main emphasis of the implementation guide is to standardise the definition of the data elements and to assist competent authorities during the implementation. In particular, the implementation guide provides the following:

  • Chapter 1: Registration and data access requirements for the User Interface and Application Programming Interface (API)
  • Chapter 2: Format for the electronic submission of veterinary medicinal products information
  • Chapter 3: Process for the initial submission and maintenance of veterinary medicinal products information
  • Chapter 4: Processes for the submission of legacy data on veterinary medicinal products
  • Chapter 5: API Technical specifications
  • Chapter 6: Practical examples

One of the major aspects the implementation guide confirms is that “The UPD is building on the existing PMS database structure with connection to the three other services of SPOR”.

As a reminder, then, SPOR is based on the four pillars of

  • Substance Management Services (SMS)
  • Product Management Services (PMS)
  • Organisation Management Services (OMS)
  • Referentials Management Services (RMS)

With the SPOR portal providing the following data management services:

  • view, search, export SPOR data
  • request new and updated SPOR data
  • translate SPOR data
  • browse relevant SPOR documentation

The UPD message format

The third important update.

A further important aspect of the UPD implementation guide is the definition of the message format for the delivery of data and documents to the UPD , which will be based on the Fast Healthcare Interoperable Resource (FHIR) message format (“The information and documents related to a veterinary medicinal product shall be submitted to the UPD via a Health Level 7 (HL7) Fast Healthcare Interoperable Resource (FHIR) message based on the terminology and reference standards available in the SPOR system.”). Using the FHIR format, from 28/January/2022 MAHs shall submit the following:

(a) the dates when their authorised veterinary medicinal products are placed on the market, information on the availability of each veterinary medicinal product in each relevant Member State, and the dates of any suspension or revocation of the marketing authorisations concerned.
(b) the annual volume of sales for each of their veterinary medicinal products.

Products placed on the market before 28/January/2022 have a slightly longer deadline and should be recorded by 28/January/2023.

In summary

The EMA is inviting interested parties to comment on the UPD implementation guide until 21/March/2021. The UPD implementation guide provides timelines, details on data exchange message formats (FHIR) and further details about the use of SPOR. Stakeholders are advised to act in a timely fashion to address any issues that this implementation guide might present.

With the above, we only touched on three of the important aspects of the UPD implementation guide. More details will follow in future blogs.

Machine Learning for the benefit of Life Sciences

Machine Learning (ML) is a form of Artificial Intelligence (AI), allowing applications to learn from the data processed. This is in contrast to programming, which follows a defined route to write a specific computer program. During the absorption of data, the ML algorithms learn to produce better, more precise ‘models’. These ML ‘models’ are an output from training the ML algorithms. Training can be performed on smaller data sets, but best results are achieved when using large data sets.

After training a ‘model’, when you provide the model with an input, you will be producing an output. For example, a data extraction algorithm will create a data extraction model. Then, when you feed this model with data, you will receive a data extraction based on the data that trained the ‘model’. In most cases this will be an iterative process, allowing the ‘model’ to learn continuously.

ML differs from data mining as data mining is based on the principle of statistics. Traditionally data mining is used on structured data, intended to demonstrate data patterns. In contrast, ML automates the identification of patterns, mainly used to make predictions. To be fair, there are some similarities as both are analytical processes and are good for pattern recognition.

Although ML is already widely used in life sciences with analysing medicinal images, to give one example, it seems in Regulatory Affairs we are trailing behind. The recent implementation of IDMP highlighted several issues with regards to data and its granularity but also where it is maintained and how it can be accessed. Many found that accessing unstructured data, usually as part of documents, is a real challenge. This is where companies can benefit from ML.

The challenges with unstructured data.

Pharmaceutical companies are required to create SPCs (Summary of Product Characteristics) and PLs (Package Leaflets) for each and every medicinal product on the market. Both documents contain the required data to keep the public and health professionals informed about substances, excipients, Marketing Authorisation Holders (MAH), possible side effects and more. But here lies the challenge: structured data is contained in unstructured documents. The implication is that the data extraction project will be abandoned or time-consuming manual more error prone processes have to be used. But both options seem unsuitable if these documents are the only place where this type of data is managed. So, are there other more sophisticated methods available?

The benefit of Machine Learning.

ML seems an ideal approach here for many reasons. First of all, with SPCs available for nearly all medicinal products on the market, a large data set is available for training the ML ‘model’. Secondly, SPCs are semi structured documents with predefined sections, which partly supports the extraction process of product name, indication, substance, excipients and other data fields. Moreover, ‘models’ have to be trained to identify different SPCs for different products from different regions, independent of whether these products are for human or animal use.

Data granularity is another challenge, specifically with IDMP (Identification of Medicinal Products) in mind. The IDMP data model for example defines the “Authorised Medicinal Product” in detail with components including but certainly not limited to “Medicinal Product Name”, “Manufacturer/Establishment (Organisation)”, “Contra-Indication” and “Indications”. Now “Name of Medicinal Product” is also part of the SPC and so are “Therapeutic Indications” and “Contra-indications”. However, the granularity of SPC data compared to IDMP data is different. Here is where ML algorithms can be of benefit. ML algorithms will learn how to interpret the data structure and extract the data in IDMP compatible format. This process of “supervised learning” is based on certain understanding of the data to be analysed. The benefits are clear: an automated process via ML to establish structured data, which then can be used company wide for analysis and future processing, whether in Regulatory, Labelling or elsewhere.

Another underestimated benefit specifically for Generics would be the ability to easily compare SPCs with the originator’s SPC. Data from both documents, the originator SPC and the Generics SPC, can be extracted and compared on data level to identify any differences that might have occurred, especially after updates following an adverse event. ML algorithms will learn the layout of both versions of the SPC, train their ‘models’ accordingly and allow for precise data extraction, which then can be easily compared. Here we might get into Deep Learning utilising neural networks but more on that in a future post.

Join us at the upcoming DIA conference, 8th to 10th February 2021 to learn more about Machine Learning for the benefit of Life Sciences.

UK spearheading Pathway for faster Time to Market

The UK is spearheading a new initiative on how innovative medicinal products can be brought to market faster and therefore made accessible to patients more quickly. In December 2020, the MHRA released new guidance documents on ILAP or Innovative Licensing and Access Pathway to clarify new opportunities for stakeholders in medicinal product development. Already operational, this initiative encourages early pipeline discussions between stakeholders. The aim of ILAP is to accelerate the time it takes to get a medicinal product to market and does not replace the Early Access to Medicines Scheme in areas of unmet medical needs. The Pathway brings together innovative approaches to support the safe, timely and efficient development of innovative products.

What are the criteria for acceptance to the new Pathway?

To take part in ILAP, interested parties have to submit an Innovative Passport application for each medicinal product. This process is open from the pre-clinical trial phase through to mid-development and the Passport itself contains a broad and inclusive definition of ‘Innovation’. To fulfill the Passport requirements, the following criteria have to be met:

  • Criteria 1: details of the condition, patient or public health area.
    a) the condition is life threatening or seriously debilitating or
    b) there is a significant patient or public health need
  • Criteria 2: the medicinal product fulfils one or more of the following areas
    a) Innovative medicine such as an advanced therapy medicinal product or new chemical or biological entity or novel drug device combination
    b) The medicine is being developed in a clinically significant new indication
    c) Medicine for rare disease and/or special populations such as neonates, children, pregnant women and the elderly
    d) Development aligns with the objectives for UK public health priorities.
  • Criteria 3: the medicinal product has the potential to offer benefits to patients
    For this criterion the applicant is expected to provide a summary of how patients are likely to benefit from the product or indication coming to market, including:
  • proposed improved efficacy or safety
  • contribution to patient care or quality of life, as compared to alternative therapeutic options.

What Regulatory Tools are utilised?

ILAP utilises Regulatory Tools supporting the following:

• Adaptive inspections
• Certifications
• Continuous Benefit Risk Assessment integrating Real World Evidence
• Clinical Practice Research Datalink (CPRD) Assisted Patient Recruitment
• Enhanced patient engagement
• Innovative and Flexible Licensing Routes
• Novel Methodology and Innovative Clinical Trial Design
• Rapid Clinical Trial Dossier Pre-Assessment

More details about Regulatory Tools including description, benefits and expected use can be found on the MHRA website.

What might the impact be on Regulatory professionals?

There are many areas that might have an impact on Regulatory professionals. One specific area worth mentioning can be found under the section “Innovative and Flexible Licensing Routes”. This Regulatory Tool has the potential to expedite timelines for review and accelerate assessment so valid marketing applications will reach opinion on approvability within 150 days of submission. This option is available for good quality marketing applications for both new and existing active substances.

The other area worth mentioning is “Rolling Review”. It is a new route for marketing applications, offering ongoing regulatory input and feedback. The process is envisaged as a phased, modular, iterative approach of evaluation.

Summary

Overall, ILAP might be the next step that supports the safe, timely and efficient development of innovative products. It is a cutting-edge approach to allow early reviews supported by an increasing number of useful Regulatory Tools that assist stakeholders to make better decisions more quickly, thus bringing medicinal products to the market faster.

UPDated – EMA updated Union Product Database implementation guide

According to the New Veterinary Regulations (NVR) EU 2019/6, the European Medicines Agency (EMA) shall establish and maintain a Union Product Database (UPD). In July 2020 the EMA published the UPD access policy (EMA/198149/2020), which outlines who gets access to which data stored in the UPD. It outlines how all parties can meet their obligations as provided in the Veterinary Medicinal Product (VMP) regulations and at the same time protect personal as well as confidential data.

But who can access the UPD?

The UPD will be open to agencies, marketing authorisation holders as well as the public. Different access levels will be provided, allowing data entry and updates where required. Considering the needs and requirements from different UPD stakeholders, UPD access levels are as follows:

  1. Full access for authorities, EMA and Commission.
  2. MAH will have access to their own MA.
  3. Limited read only access for the public (including veterinary practitioners).

The public will be able to search the UPD for product information nationally and in the wider EU. Data fields of interest include but are not limited to the product name, active substance, country of authorisation, target species, and MAH.

How will it all work?

The status of the Union Product Database (UPD) has again been updated. The release notes from the EMA have been published (EMA/556635/2020) together with additional information on which data can already been accessed. This release of the UPD makes the first components such as the API available, thereby providing access initially for National Competent Authorities (NCA). However, the functionality is limited to reading information on centrally authorised products and automatically creating MRP/DCP/NAP product information. NCAs can link to the UPD via an API to extract Centralised Authorised Product (CAP) information. NCAs can also start testing product information upload. Further information on increased functionality is planned to be released gradually throughout the coming months.

What about other stakeholders?

The Federation of Veterinarians of Europe (FVE) has very specific expectations with regards to the UPD search capabilities (FVE/20/doc/055, August 2020). The following search criteria are especially seen as relevant for veterinary practitioners:

  • Product name,
  • qualitative and quantitative composition of the pharmacologically active substance(s),
  • the pharmaceutical form,
  • countries the veterinary medicinal product is authorised in,
  • indications for use,
  • target species and dosage for each species,
  • method and route of administration,
  • contra-indications and adverse events,
  • drug-drug interactions,
  • information essential for safety or health protection,
  • withdrawal time,
  • distribution category,
  • Marketing Authorisation Holder (MAH) and
  • therapeutic group.

Although only from one stakeholder’s point of view, the benefits of a single database seem obvious.

In summary

The expectations are high, the list of demands looks excessive. But it also highlights the benefits that can be achieved with the UPD if implemented correctly with all stakeholders in mind. If combined with keyword or wildcard searching and access to SPC and PIL documents, the UPD will truly be single source of information for many – as long as all product information is actually managed within it of course.

Please feel free to contact us if you require further information.

UP-to-Date – EMA’s Union Product Database implementation guide

What is the UPD?

According to the New Veterinary Regulations (NVR) EU 2019/6, the European Medicines Agency (EMA) shall establish and maintain a Union Product Database (UPD). With that in mind, implementation acts are required laying out electronic exchange mechanism and data format, database functionality and interface/API as well as detailed specifications of the data to be managed.

The EMA recommends building a system utilising existing functionalities as far as possible. This, for example, includes the current development of SPOR (Substance, Products, Organisation, Referentials) which is applicable to both human and veterinary products. However, because of the tight time frame, the initial development will focus on a minimum viable product fulfilling only legislative requirements.

Part of SPOR is the Product Management Service (PMS) that has been modelled based on ISO IDMP (Identification of Medicinal Products), managing medicinal products for humans and veterinary use. However, PMS is slightly smaller than the full ISO IDMP. The UPD now mandates fields and entities that largely fall within the scope of PMS. However, there are a few exceptions required in the UPD that are not covered under PMS such as volume of sales or variations not requiring assessment.

So, what is the suggested content of the UPD?

The UPD has been designed to simplify data sharing from Marketing Authorisation Holder (MAH) via regulators to patients. With that in mind, for veterinary medicinal products the following data fields are considered:

  1. name of the veterinary medicinal product;
  2. active substance(s) and strength;
  3. summary of product characteristics;
  4. package leaflet;
  5. the assessment report;
  6. manufacturing sites;
  7. the dates of the placing of the veterinary medicinal product on the market.

For homeopathic veterinary medicinal products, the data fields are as follows:

  1. name of the registered homeopathic veterinary medicinal product;
  2. package leaflet; and
  3. manufacturing sites.

Furthermore, veterinary medicinal products allowed to be used in a Member State in accordance with Article 5(6) are also managed in the UPD.

Last but certainly not least, the annual volume of sales and information on the availability for each veterinary medicinal product is also managed in the UPD. This point is one that needs urgent attention from MAHs as this data has to be collected in the relevant Regulatory Information Management (RIM) systems. Further details on the format of the data to be collected can be found in EMA/CVMP/586518/2019.

What about other UPD stakeholders?

The Federation of Veterinarians of Europe (FVE) for example describes the UPD as the most important tool to increase availability of veterinary medicines for practitioners, mainly because it allows searching for veterinary products EU wide in case no suitable treatment can be found nationally (FVE/20/doc/055, August 2020). The FVE also made some interesting suggestions including the point that all veterinary products should be entered into the UPD no later than January 2022 to avoid the current status of the EudraPharm Veterinary Database, which is still seen as incomplete.

One other interesting suggestion from the FVE is to state strongly that “The Union product database must avoid duplicate input of data in different Union systems.” Moving away from ‘The Union product database should be developed…” clearly demonstrates the desire to reduce data duplication. Now why should this remind me of the “Single Place of Truth”® for Regulatory Information Management?

In summary

The Union Product Database has been welcomed by many and will certainly improve the safety, availability and maintenance of veterinary medicinal products in the EU. Furthermore, with the implementation of the NVR, of which the UPD is a pivotal part, administrative burden on MAH and regulators will be reduced although some additional information such as sales data will be required. I am looking forward to seeing more detailed UPD implementation guide in due course.

Please feel free to contact us if you require further information.

EMA provides latest on Article 57

Action required before end of January 2021.

Since 1 February 2020, when the United Kingdom withdrew from the European Union (EU), the UK has become a ‘third country’ as far as the EU is concerned. A withdrawal agreement has provided direction for the transition period, ending 31 December 2020 (European Commission, Notice to Stakeholders, 13 March 2020). At the end of the transition period, the EU rules for medicinal products will no longer apply to the UK.

What about the impact on Marketing Authorisations?

The UK leaving the EU has, of course, an impact on Marketing Authorisation Holders (MAHs). One example being that according to Article 2 of Regulation (EC) No 726/2004, the MAH must be established in the EU. Not a major impact on multinational companies, but what about a Small to Medium Enterprise (SME)? At the end of the transition period, an MAH from the UK must have the marketing authorisation transferred to an MAH in the EU with an impact, for example, on labelling and packaging.

What about access to EU databases?

On 16 October 2020 the European Commission published Commission Decision C(2020)7126, granting the United Kingdom (in respect of Northern Ireland) access to databases established under EU law. Besides information about agriculture, energy or tax, the decision also outlines database access for the pharmaceutical sector.

So, what will change?

Under section “Medicinal Product”, the European Commission outlines access to Eudralink (full access), EudraNet (partial access) but also Extended EudraVigilance, Article 57 (XEVMPD) with read only access for medicinal products authorised in Northern Ireland.

Moreover, on 1 December 2020 the EMA posted an updated guidance document EMA/520875/2020 on the impact of Brexit, especially with regards to Article 57 and the steps required by MAHs. MAHs will be able to amend EVMPD data from 15 December 2020 with review and updates of records to be finalised by end of 2020. Even with the extended deadline of 31 January 2021, the time for MAHs to act will be very short.

So what action is required by MAHs?

Maintenance of records for medicinal products outside the EEA in Article 57 database is voluntary. MAHs with medicinal product records currently referencing ‘United Kingdom (GB)’ as the ‘Authorisation Country Code’ should review their product data in the Article 57 database and, for products that will continue to be authorised by the UK with respect to Northern Ireland after 31 December 2020, change the country of authorisation to ‘United Kingdom (Northern Ireland)’ with the assigned country code ‘XI’.

The authorised medicinal product (AMP) records should be updated by submitting an extended EudraVigilance Medicinal Product Report Message (XEVPRM) with operation type ‘Update’ for the relevant EV Codes. It is worth reminding MAHs that it is their responsibility to ensure that their records in the Article 57 database are accurate.

In summary

With the UK leaving the EU, many MAHs will be required to update their medicinal product information, whether via XEVPRM messages or Variations. With an impact on product licenses, labelling and packaging, stakeholders are advised to take all necessary steps to account for the UK being outside of the EU regulatory system for medicinal products at the end of the transition period.

If you require further information, please do not hesitate to get in touch.

uNcoVeR the EU’s New Veterinary Regulations

Uncovering the New Veterinary Regulations (NVR) EU 2019/6 for Regulatory Information Management (RIM) is not quite straight forward. The NVR will become applicable from 28th January 2022, bringing additional burden but also benefits to the veterinary industry. It contains new measures for increasing the availability and safety of veterinary medicines and is one of the biggest changes to European veterinary regulations for a very long time.

Let’s have a look at the main objectives of the NVR 

  • Simplify the regulatory environment and reduce administrative burden for pharmaceutical companies developing veterinary medicines; this will be welcome news specifically for all regulatory departments;
  • Stimulate the development of innovative veterinary medicines; certainly welcome by everybody dealing with or concerned about animals;
  • Improve the functioning of the internal market for veterinary medicines;
  • Strengthen EU action to fight antimicrobial resistance through specific measures ensuring prudent and responsible use of antimicrobials in animals.

What are the key benefits of the NVR?

  • Increased availability and access to safe and high-quality veterinary medicines; probably the most important benefit of the NVR for everybody concerned about animal welfare;
  • Reduced administrative burden and better incentives for pharmaceutical companies developing new and innovative veterinary medicines; although a benefit not immediately seen by the public, any reduction in administrative work will finally filter through the medicinal product life cycle;
  • New and enhanced rules to keep antimicrobials effective.

But what does it all mean to Marketing Authorisation Holders (MAH)?

There are clear wins for MAHs such as the removal of renewals as veterinary medicinal products will be valid for an unlimited period of time. The benefit will be that even if products are not marketed for a long time, marketing authorisations will not lapse. Please note that there are exceptions to this rule.

Other changes include that MAHs registering marketing applications for generic veterinary medicinal products are not required to submit documentation on safety and efficacy (as long as certain criteria are met). This will streamline the marketing authorisation process for Generics and benefit animals and animal owners alike.

What about variations though?

Variations are another area that has been simplified. From Type Ia/Ib and Type II to two simple types of variations: variations that require assessment and variations that do not. The EMA gave recommendations on the list of variations not requiring assessment (EMA/CVMP/263581/2019) based on the following criteria, listed in Article 60(2) of Regulation (EU) 2019/6:

  • the need for a scientific assessment of changes in order to determine the risk to public and animal health or to the environment;
  • whether changes have an impact on quality, safety or efficacy of the veterinary medicinal product;
  • whether changes imply no more than a minor alteration of the summary of product characteristics;
  • whether changes are of an administrative nature.

What does it mean for Regulatory Information Management though?

Changes even to variations that do not require assessment still have to be recorded in the Union Product Database (UPD), one of the major additions coming with the NVR. RIM solutions have to be adapted to cater for a change in handling variations, license validity and most of all the UPD itself. Furthermore, new data fields will be required to comply with latest regulations. The ability to collect annual volume of sales and information on product availability are only two examples. IDMP and SPOR are already advancing for management of the human medicinal product life cycle. The veterinary medicinal product life cycle would certainly benefit from using a similar, if not the same approach although it is already known that certain data fields are not covered by either.

So what next?

I consider the least favourite option to be doing nothing. The NVR will come, and it will come quickly. Adapting to new regulations is never straight forward and the NVR is no exception. Processes have to change to cater for a change in handling variations and additional data fields need to be implemented to be able to feed into the UPD. The time frame for NVR implementation is short and MAH are advised to act promptly.

Regulatory Information Management (RIM) for Veterinary

With the new veterinary regulations Regulation (EU) 2019/6 coming into effect in January 2022,isn’t it time to look at the benefits of streamlining veterinary product management?  Wouldn’t it be beneficial to get support for submission planning, drill deep down into data using Analytics, minimise manual more error prone tasks and at the same time increase efficiency and data quality?  Many pharmaceutical companies have implemented Regulatory Information Management (RIM) solutions, benefitting from improved business processes, data sharing (specifically across different business units) and shortening their timelines to submit marketing applications.  Why should companies manufacturing and managing veterinary products not be able to achieve the same?

For some time, VNeeS has been the preferred submission format in Europe with the latest guidance version 2.7 to be implemented in October 2020.  Already, with the implementation of Step 7, the VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products, GL53) provided details of recommended electronic file formats.  In contrast to the eCTD (electronic Common Technical Document) for human drugs, PDF/A has been favoured.  PDF/A is an ISO standardised version of PDF (Portable Document Format), especially used for archiving electronic documents; however, PDF/A prohibits features such as external content references and encryption.

Regulatory Information Management can of course assist during the process of document creation, management and archiving, whether these documents are PDF/A or any other format. This already provides benefits of a single place of access across business functions, the ability to use and harmonise document structures, as well as data security. The real advantages though come from the ability to plan and manage the entire submission lifecycle via project templates, increase data consistency via the ‘single place of truth’ and synchronise business processes via the use of technology. Moreover, with management of multiple species per product and the addition of medical devices for animals, Regulatory Information Management suddenly becomes a viable option for companies that would like to increase their productivity. RIM can assist with secure data access, management of global product portfolios and task automation to bring life saving products to the market faster.

 Samarind RMS is one of these options.

Please feel free to contact us with any questions or if you require further information.