Translation requirements for generics in the EU

As pharmaceutical innovations become increasingly difficult and expensive to achieve, and as patents expire on blockbuster drugs, generic drug manufacturers have become one of the bright spots in the pharmaceutical industry. By developing “bioequivalent” medicines of original medicines for which patents have expired, these companies bypass many of the costs to bring original innovations to market, shaving 20-90% off the retail price of the drugs they resemble.

Given the strained health care budgets across most of Europe, it’s no wonder that producers of generic medicines see a bright future. At the moment, generic medicines in Europe represent just under 50% of the whole pharmaceutical market by volume, but only about 18% of the total cost.

Generic medicines are developed to be the same as the original innovative medicines, also called originators or originator medicines. They share the same active substances (the actual element with the desired therapeutic impact) as their reference medicines, and are used at the same doses to treat the same diseases. Generics often differ in their inactive ingredients, also called excipients, such as colorings, name, appearance and packaging.

Although generics are subject to the same rigorous authorization requirements as the original patented drugs, it’s a standard practice to borrow from the original drugs’ translated product information — requiring somewhat different workflows for authorization and translation than patented drugs.


Centralized vs. decentralized product authorization

Like their reference medicines, generics need to follow a process of authorization in individual countries before they can be brought to market.

Generic drug makers may apply for the centralized authorization process managed by the London-based European Medicines Agency (EMA), which will result in one single marketing authorization valid in all European Union (EU) countries as well as Iceland, Liechtenstein and Norway (EEA-EFTA states). Or they can use the decentralized procedure (DCP), where authorization is sought simultaneously in multiple EU countries, with one serving as the reference member state, selected to prepare draft assessment documents and submit them to all other concerned member states. Generic producers may also choose the mutual recognition procedure (MRP), whereby an assessment and marketing authorization of one member state should be mutually recognized by other states.

In practice, most generics in Europe are authorized via the DCP and MRP procedures. The EMA will automatically provide access to their centralized procedure for generics, only if the reference medicine was also authorized centrally via the agency. One other case is if the generic medicine provides a significant innovation, in which case the EMA will accept applications also for generic versions of medicines originally authorized via the national, MRP or DCP procedures.

In fact, 82% of all authorization applications finalized via the decentralized procedure during 2012 were related to generics. In the case of all finalized mutual recognition applications it was 64%, compared to only some 30% of applications in the centralized procedure that were related to generic medicines during 2010-2012. See Figure 1 for more details.

The pharmaceutical industry in Europe experienced a watershed moment in June 2013 when the EMA approved the first biosimilars — the generic versions of complex biological medicines — after concluding they are of equal quality, safety and efficacy to the original medicine. This comes at the time when the first original biotherapeutics — biological medicines made by or derived from a biological source, such as a bacterium or yeast — have seen their data protection and patents expire.

This decision has opened up the huge market for monoclonal antibodies to generic producers, after a long period during which drug companies argued that biosimilars are not identical and carry higher risks for patients. Which is also why no biosimilars have so far gained a regulatory approval by the Food and Drug Administration in the United States.


Marketing authorization process

While the product authorization process is roughly the same for generics and original drugs, generic manufacturers enjoy a somewhat simplified process for marketing authorization of their medicines (Figure 2). Since the reference medicines are already authorized, generic manufacturers don’t need to prove the efficiency and safety of the active substances their versions contain. Instead, they must prove the generic medicine is comparable to the reference medicine. As a result, generic manufacturers bypass the expense of conducting preclinical tests or clinical trials and translating their results.

A critical component of any marketing authorization is the product information, or in other words the summary of product characteristics (SmPC), advising health care professionals and patients on safe and effective uses, and serving as the basis for package leaflets.

Along with the product packaging, these SmPC-based materials always need translating. If the manufacturer is pursuing the centralized authorization process, the product information must be submitted in all EU languages plus Icelandic and Norwegian. Decentralized or mutual recognition procedures only require languages of the selected target countries.

Generally speaking, the generic’s SmPC should be in “all relevant aspects consistent with that of the reference medicinal product except for indications or dosage forms still covered by patent,” to quote the EMA’s published requirements on the subject. In practice, this means the original drug’s SmPC, labels and packaging are taken as the source and updated with the generic drug’s specifics, for the original English content as well as the translations.

Normally, the generic’s updated SmPC would describe differences in excipients used. Any additional precautions, which would be a result of the specific excipients used, must be described on the label and in the package leaflet of the generic medicine. Similarly, if the reference medicine is still enjoying patent protection for some of its indications, these cannot appear in the product information of the generic.

These process variations often apply in the case of hybrid medicines, meaning generic medicines that are presented with a different strength or with a different route of administration compared with the reference medicine. Hybrids also include versions with a slightly different purpose, such as a limited indication that will allow the medicine to be used without a prescription. While the authorization process is similar to generics, hybrid medicines sometimes need additional tests before authorization in the EU, such as clinical trials that would test their actual efficacy.

In many ways, translating product information for generic medicines is no different from translating patented medicines. But there are a few practical considerations.


SmPC consistency

As a general rule, the SmPC and other product information relating to the medicine should closely follow the reference medicinal product previously authorized in the EU. The translated product information for already authorized medicines is normally freely available online for all the languages.

Using these preexisting translations as reference material is a must, with a focus on consistency between the generic and patented versions. Sections of the product information which are identical between the originator and the generic drug must use the corresponding translations from the reference medicine, correcting for any obvious translation errors. When submitting, drug makers provide the source English and all the translated SmPCs for linguistic review, with changes tracked in the English version highlighting specific deviations from the reference product information.

The main point of reusing the original drug’s product information is to build on existing knowledge of the drug for the market. There is little sense confusing patients and health care professionals alike by describing the drug and its usage in slightly different terms, only because the manufacturer of the drug is different, when active substances are the same. This rule is also designed to make the process of linguistic review of the translations, conducted by the agency, more efficient. This simply helps avoid any unnecessary linguistic review exercise.


Using QRD templates

Quality Review of Documents (QRD) templates are Microsoft Word documents that provide the official wording of the SmPC, labeling and package leaflet in all official European Union languages plus Icelandic and Norwegian. These templates are developed and periodically updated by the EMA’s Working Group on Quality Review of Documents for the centralized procedure as well as the mutual-recognition and decentralized procedures. The centralized procedure’s QRD template is currently on its ninth version, while the MRP and DCP template has been updated to version 3. All of these templates may be downloaded at in Word and PDF form, as seen in Figure 3. The most recent update, for instance, included recommendations of the new European pharmacovigilance regulation and incorporated new sections on reporting side effects or suspected adverse reactions.

The translated SmPC should use the current versions of the local-language QRD templates, if the relevant information is available. That is, while the reference medicine may use an older QRD template — even the latest version filed with the EMA during its patented period on the European market — the new generic’s product information should follow the current template. This process of “harmonization” will involve careful word-by-word review of the existing translated product information of the patented medicines, and comparison with the latest QRD template for the given language.

While this may sound like a daunting task, the English source will normally have undergone the same process, enabling a comparison of the extent of changes made to the source QRD version by the generic drug manufacturer. If, however, the relevant information from the reference medicine’s SmPC is not available, this part of the SmPC should not be updated to the latest QRD template for the generic, as the content of the SmPC must remain consistent throughout.


Generic manufacturer specifics

While generics contain the same active substances as their reference medicines, and are used at the same dose to treat the same condition, they are not exact replicas. As a result, it’s crucial to track every single difference between the original and generic SmPCs, such as the excipients, the name of the medicine, its appearance, description and its packaging.

Tracking such details can be challenging in the case of MRP or DCP procedures, especially when a generic is based on a reference medicine that was previously authorized on a national basis. SmPCs for such a reference medicine may, for example, describe different indications in individual EU states, referred to as “non-harmonized originators.” Generic manufacturers must submit the same application file with the same SmPC in all concerned member states. This forces some hard calls on harmonization of the product information to ensure identity of SmPCs between the generic and reference medicines for individual countries.

Since so much about the generic medicines is modeled on their reference drugs, it is easy to get lost in the process, and be too focused on spotting, analyzing or reading into any differences. While consistency is critical, it is important not to lose sight of the core objective: providing accurately translated product information that complies with the current European legislation, and uses the approved templates, language and terminology.


Timelines and naming

Patents for medicines in the European Union are granted for a period of 20 years, and can be increased by up to five additional years through a supplementary protection certificate (SPC) designed to encourage innovation by compensating originator companies for the time and expense required to obtain regulatory approval.

Companies are also covered by data exclusivity, which runs parallel to actual patent protection. There can be no generic drug application and no disclosure of regulatory data to a competitor during the period of data exclusivity. In the EU, there is currently an 8+2+1 formula in place for data and marketing exclusivity. This means eight years of data exclusivity since the initial authorization of the reference medicinal product, during which no generic applications may be filed. This is followed by two additional years of marketing exclusivity, during which generic applications  cannot be yet approved. There is then one extra year of protection if there are new therapeutic indications with a significant clinical benefit. This means that generics can only be placed on the market ten or 11 years after the authorization of the reference medicinal product, depending on the applicable exclusivity period.

Innovative drug manufacturers work hard to maximize the length of patent protection and to keep cheaper generic versions off the market. In a practice called “ever-greening,” they try to obtain new patents for old compounds, on the strength of new uses, indications, dosages and changes in formulation, color or markings — relatively small modifications or incremental innovations rather than major boosts in the efficacy of the existing medicine.

Meanwhile, generic makers start working in earnest on preparing the generic version many years before the original drug’s patent is due to expire. The marketing authorization phase is a relatively fast process, and similar in steps and duration to the process required for innovative drugs.

As with innovative medicines, there is a short window of five days between the final Committee for Medicinal Products for Human Use opinion and the requirement to provide the SmPC translations into all the required languages. Therefore, the translation process should begin well in advance of the opinion, typically around day 165.

Coming up with a new name for the generic is one of the most exciting, and trickiest, language aspects of the authorization process. Each innovative drug will have its own official generic name in addition to the invented trade brand name, under which it is sold. After years on the market, the original medicines have established brand value for the trade name, and they typically continue to promote their branded products after the patent expiry, even if now at discounted prices. Generics may not use the patented product’s trade name, but they may use its generic name, or develop their own trade name.

Generic names are often a shorthand version of the medicine’s chemical name, structure, or formula. The World Health Organization administers these generic names via the so-called International Nonproprietary Names (INN). Medicines from the same therapeutic or chemical class are normally given names with the same stem. Trade names, on the other hand, are designed to be memorable and often serve to outline the drug’s characteristics or purpose. Sometimes they are a shortened version of the drug’s generic name.

It is of course necessary that generic and trade names are unique in order to prevent one drug from being confused with another. To that end, the EMA has developed a process whereby it reviews and approves, or rejects, all proposed new names, via their Name Review Group (NRG). This is a thorough process, and applicants are encouraged to submit up to four names to the agency preferably four to six months prior to the planned submission date of the actual authorization application. The NRG is chaired by an EMA representative and is composed of representatives from member states of Southern, Central, Northern and Eastern Europe to allow for the various language groups.

The generic medicines must use a single name, regardless of the process of authorization. This may be either an invented name not liable to confusion with the common generic name, or a common name or scientific name (normally INN) accompanied by a trademark or the name of the marketing authorization holder.

For instance, the generic name of the blockbuster brand medicine Plavix, marketed by Bristol-Myers Squibb and Sanofi, is clopidogrel, and that is also its INN name. The EMA has approved multiple generic versions of the drug, such as Clopidogrel Teva Pharma B.V., Clopidogrel Mylan or Clopidogrel Krka. But it is also marketed by Krka under the brand names of Zylagren or Zyllt.

Generics are one of the most exciting and fastest-growing segments of the EU’s pharmaceuticals industry. Although generics can bypass the years of research, clinical trials, product information development and, let’s face it, waiting times that innovators undertake, they are still beholden to the EU’s high standards for product authorization and clarity across all target countries. Although they can certainly enjoy efficiency benefits in reusing the reference medicine’s SmPC, generic manufacturers must not expect to rush through the translation process.