The animal health industry has long voiced concerns over some of the difficulties of marketing products in the European Union. These include:
- High administrative burden produced by the need to translate and produce packaging and product inserts in national languages for smaller markets
- Work required for submitting variations and the time they take getting approved
- Requirements for submission of Periodic Safety Update Reports (PSURs)
In its most recent legislative endeavor—the Veterinary Medicines Legislation 2019/6—the European Commission has sought to address many industry concerns. The legislation aims to reduce the administrative burden for veterinary medicines manufacturers and improve availability of veterinary medicine products throughout the European Union while at the same time ensuring the safety of those medicines. It is intended for implementation across the European Union without national interpretations. This legislation has been more than nine years in the making.
At the inaugural PDA Europe Aseptic Animal Health conference held virtually in October 2020, Dutch Medicines Evaluation Board Veterinary Medicines Bureau Head Frank Verheijen gave a regulator’s perspective on nuances of the legislation. He also discussed what is involved in its implementation including how much work is left to be completed.
“Although the text of the regulation is finalized and it was published almost two years ago, there is still a lot of work to do for the future,” he emphasized. “The main regulation has been finalized, but in this regulation, there are specific items referred to as ‘implementing and delegated acts.’ The Commission and the member states are still working on these. They are particularly important because they provide more detail on what the future will bring.”
Verheijen commented that “for both marketing authorization holders and for national competent authorities there is a lot of work to be done before the 28th of January 2022” when the regulation goes into effect.
[Related: Do you manage a quality and compliance team for a veterinary medicine company? Consider test-driving our Enforcement Analytics platform.]
A Look at the EU Market
The European Union consists of 27 member States. Together with Iceland, Norway, and Liechtenstein, they form the European economic area. The new regulation will be applicable without national interpretations in all those 30 countries. In total, there will be 24 official languages. It will replace directive 2001/82, which was based on the human directive 2001/83 with identical requirements, resulting in a relatively high administrative burden for the veterinary industry.
The veterinary market is much smaller than the human markets—less than 5% that size. There are some other differences, for example, there is no reimbursement for public health insurance, therefore there are lower prices and margins for veterinary medicinal products. It is more difficult for marketing authorization holders to get a good return on investment. Lack of product availability in small markets is one of the big issues, “because if you have to produce, for instance, products in packaging with the national language, then in a small market the investment is not worth it,” Verheijen explained.
He noted that developing new legislation in the European Union is bound by strict legal rules and “therefore is a very long process.” For instance, the work started on this regulation in 2009 with an impact assessment that took almost three years. The Commission started the drafting process in 2012. The first draft was published in September 2015, under the Italian presidency.
The veterinary market is much smaller than the human markets
After the draft was published, it took more than three years to negotiate with all the member States in the Council Working Party to come to the final document. The final text of the draft was published December 11, 2018. The legislation will apply as of January 28, 2022. The Commission published a summary of the main objectives of the legislation (Figure 1.)
Embracing the 1,1,1 Principle
Verheijen addressed the key changes in the new regulation as compared to the current directive.
First, the centralized procedure will be open for all applications, including generics. “This is basically the 1,1,1 concept as promoted by the industry,” he pointed out. “This means one dossier, one assessment, and one decision. If the decision is positive, companies have the marketing authorization for all member States in the European union.”
The intent is for the 1,1,1 process to lead to less administrative burden during the lifecycle of the veterinary medicinal products, “because as a market authorization holder the company only has to communicate with the European Medicines Agency and not with all the independent national competent authorities.”
The legislation also provides for longer protection periods for technical data and for major variations. “Hopefully this will lead to the development of products for minor species, because if you, as a marketing authorization holder, include a minor species in the Summary of Product Characteristics, or SPC, and indications for minor species, this will result in a prolonged detection period as well in major species,” Verheijen predicted. “Hopefully, this will lead to a better return on investment and is an incentive for innovation and increased availability for products for minor species.”
This means one dossier, one assessment, and one decision
Industry has indicated that the current requirements for packaging are an extremely high administrative burden. It can be quite costly because of the requirements that the packaging be in each national language in combination with all the national requirements to be put on the packaging.
“The Commission simplified these requirements,” he explained. “For example, pictograms are allowed and there is only limited information on the direct packaging. Member States can accept foreign languages on packaging. Furthermore, there will be no national requirements in the future.”
The product leaflet must be made available, and it must be included in the packaging. In combination with the aspect that Member States can accept foreign languages, this opens the opportunity to produce bigger batch sizes and to provide only product leaflets in the national language together with packaging in a different language—if Member States accept that. It is hoped that this reduction of costs for marketing authorization holders will improve product availability in smaller member states.
New, Interactive Databases
An especially important development in the future that is intended to have tremendous impact is the introduction of four interactive European Union databases (Figure 2).
These interactive databases are intended to create transparency for the public and are fundamental to the successful implementation of the regulation.
They are designed to increase the availability of information because the public will be able to find it in the Union Product Database. For example, veterinarians will be able to find information on the existence of products that have a market authorization in their market, and through the cascades—a system allowing off-label use—will be able to use those products for special indications. In addition, there will be a standardization of information.
Verheijen noted that sales data should also be recorded by the marketing authorization holder into the Union Product Database (UPD). This will give insight into the availability of veterinary medicinal products in the member states. For more on the UPD and its use, click here.
Regarding the development of the Union Product Database that EMA is responsible for, there is only a limited budget from the Commission and there is a deadline for delivery by January 28, 2022.
These interactive databases are intended to create transparency for the public
Due to these restrictions, EMA will not be able to build a complete functional database. Instead, it will deliver what is referred to as the “Minimum Viable Product,” which fulfills only the legal requirements. There will be no additional functionality.
The timely development of the database in combination with electronic application forms, however, is crucial for the date that the regulation comes into force. “So, it is understandable that EMA is only able to deliver a product according to the minimal viable requirements,” Verheijen commented.
With respect to the database on manufacturing and wholesale distribution, there is a question if the current available information is detailed enough to fulfill the criteria of article 91. The question is what will be done if some information is missing, or how to update dossiers of old products.
Changes at a Distance
Also to be published is an extensive list of variations that do not require an assessment. The list is expected “soon.” These variations are to be included directly in the Union Product Database by the marketing authorization holder. “Since they do not have to apply for a variation but can do the work themselves, hopefully this will lead to a reduction in the administrative burden,” Verheijen said.
He also pointed out that another important development resulting from this regulation will be the harmonization of existing old products, noting that they are nationally authorized products.
Verheijen explained that the differences in the SPC with older products are often marginal and after harmonization these products will be upgraded to the Mutual Recognition Procedure status.
“This will be addressed by the CMDv—the Coordination Group for Mutual Recognition and Decentralized Procedures for Veterinary products—and it should be as much as possible an administrative procedure. There are some questions regarding what to do with the quality part of the dossier, but hopefully CMDv will deal with this in a pragmatic way.”
After harmonization of products of the same company are completed there will be what is called “class harmonization,” because the regulation states that generics should follow the harmonized SPC of the originator product. “This might give some troubles in practice, but we will find out how it will work,” the Dutch Veterinary Medicines Head commented.
Veterinarians will be able to find information on the existence of products that have a market authorization in their market
In addition, there will be no PSURs (Periodic Safety Update Reports) anymore because PSURs will be replaced by a signal detection process. In addition, the sunset clause will not be applicable anymore. “If, as a market of authorization holder, you have reasons for not bringing a product to a certain market, the market authorization states then will not reject it from a legal standpoint due to the sunset clause. So hopefully this will also contribute to reduction of administrative burden and will increase availability of veterinary medicinal products.”
To combat antimicrobial resistance there will be a list with antimicrobials to be reserved for human use that are critical antibiotics, i.e., last resorts. They are used to treat infections in humans that do not respond to the regular antibiotics.
There will be GMP requirements for inactivation of autogenous vaccines. Autogenous vaccines have their own article in the new regulation and their usefulness is recognized, but only inactivated autogenous vaccines can be used, Verheijen explained. “That means that there should be some quality requirements for the inactivation.”
There will be rules for what are known as sales at a distance, i.e., Internet sales. There will be a common logo for companies that start this practice to inform customers that their activity is legitimate. This can also be cross border for products without a prescription. In addition, there is an article on parallel trade and there will be a review of rules for environmental risk assessment and research done to see if there is an option for a monograph system to replace the current individual environmental risk parts of the dossier.
Reducing Administrative Burden
Although the text of the regulation is finalized and it was published almost two years ago now, there is still a lot of work to do for the future, Verheijen said.
He noted that the main regulation has been finalized, but in the regulation, there are numerous specific items subject to implementing and delegated acts. The Commission and the Member States are still working on these acts (see the progress to date here).
Currently, the process is that expert groups of the EMA come with advice that serves as input to the committees (see the advice to date here). The drafts will be discussed in the standing committee together with the Member States. When there is an agreement or after voting, the Acts will be adopted and published on the Commission’s website. These delegated and implementing acts are particularly important because they provide more detail on what the future will bring.
By far, the biggest change for the future is the introduction of the Union Product Database and some other databases for national competent authorities. It is hoped that this will lead to a reduction of administrative burden and an increase in transparency for the public.
There will be GMP requirements for inactivation of autogenous vaccines
The idea behind the UPD concept is reduction of administrative burden for both marketing authorization holders and national competent authorities. It will lead to an improved data quality and increased transparency for the public and for veterinarians or other interested parties. It is being designed as a relational database model with centralization of all data on veterinary medicinal products in a standardized way with a new uniform data language.
The principal will be single data entry for multiple use, “so that should be good for data quality and for administrative burden,” Verheijen said. “It is intended to be a smart and efficient system for data entry and document transfer.”
SPOR Project Key to Success
The success of the UPD will depend on the progress in the SPOR project. SPOR is a project for a standardization of information. It stands for Substances, Products, Organizations, and Referentials. Each has a management system.
Organizations include the applicant, the Marketing Authorization Holder, manufacturers, and importers for both products and substances. Referentials include the species, drug form, route of administration, the ATC Vet code, and more. These are databases dedicated for those items (more information is available here).
Clear identification of veterinary medicinal products starts with the identification of the active ingredients. Therefore, there is a project started called ISO IDMP—International Organization for Standardization (ISO) standards for the Identification of Medicinal Products (IDMP)—to develop a European Union network-wide substance database for active ingredients.
EMA is implementing the standards in a phased program based on the SPOR master data (more information is available here).
The project is governed by a group of national competent authority experts from the Substance Validation Group who ensure the data quality is fit for use. Initially, it will be developed for human products, but it will be also applicable for veterinary medicinal products, certainly for pharmacological active ingredients. Recently a veterinary subgroup was formed to do the same work for veterinary vaccines.
Summary of Present Situation
To summarize the current situation, implementing Acts of the UPD and variations that do not require an assessment are not finalized yet. They are expected soon.
The work on the UPD has started and is in full progress. Hopefully, the final text of the Act will not require too many changes in the work already done.
The functionality of the UPD will initially be limited.
It is crucial that the information that is gathered in the SPOR project is delivered on time, because it is needed to populate some parts of the UPD.
“I wish you all good luck with that,” Verheijen said. “Whether you work at a large or small pharmaceutical company or a large or small national competent authority, we all should realize that we are in this together, that we have to work in an open and transparent way to make the implementation of the new regulation a success.”
[Related: Do you manage a quality and compliance team for a veterinary medicine company? Consider test-driving our Enforcement Analytics platform.]
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