According to the US FDA, a generic drug (short: generics) is defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use". In other countries other definitions may apply.
In most cases it means that patent protection for the original drug has expired, which allows other manufacturers to produce and sell their own versions of the original drug.
Generics: opportunity and threat
Generics are an opportunity because they create competition, which brings the prices down, also of the original product, and enhance availability. Lower prices make it possible that good drugs become available to users that could not afford the expensive original drug. For producers generic drugs allow reducing production costs and be more profitable. Enhanced availability means that generic products become usually available through more distribution channels than the original products. Typical examples of veterinary drugs are flea+tick spot-ons containing fipronil (clones of FRONTLINE TOP SPOT, the original product). For years the original product was available only through selected veterinary doctors and pharmacies. Generic brands are now available through numerous OTC channels.
The threat comes from two sides, parasite resistance and poorer quality. The availability of generics of a drug with a specific active ingredient increases the use of this active ingredient against particular parasite species (e.g. fleas, flies, ticks, worms, etc.). From the global perspective, this means that the selection pressure against particular parasites increases, and this is the major factor that drives resistance development. Regarding quality, as the number of manufacturers and distributors increases, the risk that some manufacturers work less seriously that the original manufacturer (mostly a multinational company) is significant. This regards not only physical quality of the product, but also service and medical advice. In the case of fipronil generics, if someone buys it in a supermarket or online, medical advice is likely to be zero, which is not always the best option.
Are generics really worse than the originals?
It is not true that original products are better than generics. Generics are not necessarily les effective, less safe or less reliable than original products. Sometimes they are, sometimes not, it depends on numerous factors. There are examples of both. To understand why, you need to know how things work in the veterinary industry and elsewhere.
Generic active ingredients in antiparasitic drugs
Original, patent protected active ingredients in veterinary drugs have usually two possible "owners":
- the same Animal Health (AH) company that discovered it, developed a veterinary drug out of it, and manufactures and markets the veterinary drug;
- another company that, for whatever reason, discovered it but licensed its development and marketing to another AH company. This is the case for numerous agrochemical companies that are not active in AH: they develop and market their own products for crop protection, but license out the veterinary use of their active ingredients to an AH company.
In the past, most AH companies where part of larger agrochemical or pharmaceutical conglomerates that discovered, developed and marketed their own active ingredient in all major markets, including AH, e.g:
- BAYER (cyfluthrin, febantel, flumethrin, imidacloprid, praziquantel, etc),
- MERIAL (fipronil, ivermectin, clorsulon, etc),
- NOVARTIS (now ELANCO) (cyromazine, dicyclanil, fluazuron, lufenuron, monepantel, pyriprole, triclabendazole, etc),
- PFIZER (now ZOETIS) (doramectin, pyrantel, selamectin, etc).
Within these large multinationals, AH was always the smallest part (1-5% of the total business) of the pharmaceutical and/or the agrochemical business. Nowadays, most AH multinationals have been divested from their big brothers, sometimes losing the direct access to the R&D pipelines of the large multinationals. This is the case for ZOETIS (recent spin-off from PFIZER), MERIAL (spin-off from MSD and Rhone-Mérieux in the mid 1990s), CEVA (spin-off from SANOFI in 1999), etc. BAYER and ELANCO are two of the few AH companies that remain inside a larger pharmaceutical and/or agrochemical conglomerate. Others (e.g. VIRBAC) were never part of such large chemical conglomerates. And numberless other former AH companies have simply disappeared, swallowed by larger ones: COOPERS, HOECHST, ICI, ROUSSEL-UCLAF, SHELL, SHERING-PLOUGH, SMITH-KLINE, SQUIB, etc. One of the latest examples is the recent aquisition of NOVARTIS AH by ELANCO.
These "smaller" AH-multinationals that dominate the veterinary market today have one problem: they are too small for running large screenings programs for the discovery of new active ingredients. Since real innovation depends to ~90% on new active ingredients, they tend to license them out from other companies that are not active in the AH market, usually in an exclusive agreement. Although this happened already in the past, it was rather the exception than the rule. In the meantime, most new active ingredients introduced in the AH antiparasitic market in the last decade are licensed, e.g.
- Afoxolaner (NEXGARD) introduced by MERIAL was first described by DUPONT DE NEMOURS
- Dinotefuran (VECTRA) introduced by CEVA was first described by MITSUI
- Fluralaner (BRAVECTO) introduced by MERCK ANIMAL HEALTH (formerly INTERVET) was first described by NISSAN
- Indoxacarb (ACTIVYL) introduced by MERCK ANIMAL HEALTH (formerly INTERVET) was first described by DUPONT DE NEMOURS
- Metaflumizone (PROMERIS, in the meantime dropped) introduced by PFIZER (now ZOETIS), was first described by BASF
This process is likely to continue and perhaps to become the rule instead of the exception.
What happens when an original active ingredient becomes generic, i.e. loses patent protection?
The more successful an original active ingredient has been, the faster generics will be introduced. Who does it? Traditionally chemical companies that are specialised in manufacturing generic active ingredients; they do not search for new active ingredients themselves, and are mostly not directly involved in the marketing of finished drugs or pesticides. Some produce also generic formulations (finished products) but do not market them, and some may even market them directly as well. There are numerous chemical companies that do this (e.g. in Ireland, Israel, Rumania, Russia), during the last years particularly in Brazil, China and India. These companies monitor the markets and start working on generics of successful active ingredients years before patent expiry to throw them into the market as soon as possible after patent expiry.
The original manufacturer has several options to react to this threat. One is to offer their own active ingredient to potentiallly interested competitors. They may even offer their original finished product, which then will be sold by the competitors under their own brand, although it is exactly the same as the original brand. Original manufacturers usually claim a higher quality and a more reliable supply than the generic manufacturers, which is often true. But they also ask also for a premium when compared with the generic manufacturers. But the original manufacturer may also do "the opposite": let the generic manufacturers, at least one of them, produce their original active ingredient, i.e. they outsource production of the active ingredient, and maybe even the finished product. This way they save costs, because generic manufacturers can do the same job in China, India or elsewhere for a fraction of the costs in the USA or Europe.
Perhaps the generic a.i. was exclusively licensed to one AH company by a third non-AH company, which is the one that loses its patent protecion. The AH company may now source it from a generic manufacturer, or the non-AH company may now license it out to other AH-companies, etc. Every mix is imaginable.
In all cases, entry of generics into the market mean decreasing prices for all brands, both the original and the generic ones. When ivermectin lost patent protection in the 1990s MERIAL increased the price of their original products (mainly IVOMEC) for the price-war to start at a higher level. Initially this worked well for them, but did not stop the subsequent price erosion.
But the bottom line for a user is that when you buy an original product that has lost patent protection, or a generic copy, you mostly don't know who manufactured the active ingredient and where it was produced. An this is one of the reasons why it is not possible to say whether original products are better than generics or not.
Formulations of generic active ingredients
Finished vererinary antiparasitics contain not only active ingredients, but also so-called inert ingredients. They are called inert because they do not contribute to the efficacy of the product, at least directly.
Altogether the active ingredients and the inert ingredients build the formulation. Each veterinary (or human) medicine or parasiticide has its own formulation, i.e. its own recipe or composition. For many products, not only the composition is important, but also the way and sequence the ingredients are mixed together during manufacturing.
Particular medicines or pesticides sometimes contain a mixture of different active ingredients. This is usually done to target more parasites species, i.e. to reach a broader spectrum of activity.
The amount of active ingredient in a particular product varies a lot. It ranges between 1% or less (e.g. injectables with macrocyclic lactones) and more than 50% (e.g. some feed additives or some concentrates for spraying or dipping, etc). For additional information read the article in this site on delivery forms.
The inert ingredients that can make up to 99% and more of the finished product are often not only just passive ingredients (e.g. water as solvent in a liquid product, or a cellulose derivatives as binder in a tablet), but accomplish several functions that can be essential for product efficacy, safety and quality. Such inert ingredients can be e.g.
- Dispersants: keep particles suspended and prevent their settling or clogging.
- Emulsifiers: encourage the suspension of one liquid in another one (e.g. oil in water).
- Stabilizers: prevent chemical reactions between the ingredients.
- Preservatives: prevent the growth of undesired microorganisms in the product.
Inert ingredients can also have a significant influence on whether a finished parasiticide is irritant to the eyes or the skin, flammable, explosive, corrosive, etc. Formulations are therefore often decisive for safety, stability and even efficacy (spreading over the hair coat, solubility in water, etc. of a product, tolerance, etc.). Often they are not disclosed and the exact composition of a drug remains a trade secret known to the registration authorities but not disclosed to the general public. However, nowadays it is quite easy for most companies to find-out the compositionof any formulation and to reproduce it for a generic product.
Formulations can be also patent-protected, which allows to prolong exclusivity over particular uses of an active ingredient whose patent has already expired. However, patens on formulations can be filed by "everybody", not only by the discoverer of the active ingredient. In fact, it happens regularly that the discoverer "forgets" to protect some uses in the original patent and somebody else that finds it out and files a separate patent on this "forgotten" use.
In the context of original vs. generic products, when an active ingredient loses patent protection, everybody can use it to manufacture drugs. There are two basic options: manufacturing and selling exactly the same formulation as the original product, i.e. a generic formulation of a generic active ingredient; or using the active ingredient to develop more or less new formulations or delivery forms.
Generic formulations with generic active ingredients
Lets take the example FRONTLINE TOP SPOT, a spot-on for dogs and cats against fleas and ticks that contains 9.7% fipronil. Any company that produces such a spot-on with the same active and inert ingredients can get very quickly a product registration claiming similarity with the original product. In many countries the company has to proof bioequivalency, i.e. that the generic product administered to the target organism (in this case dogs and/or cats) behaves as the original product, which is usually is rather easy and cheap to achieve.
Numerous companies have done this, either with FRONTLINE TOP SPOT, or with some of its follow-up products like FRONTLINE TRITAK, FRONTLINE PLUS, etc. Not only manufacturer's of generic products have done this (e.g. CEVA, CHANELLE, VETOQUINOL, VIRBAC, SERGEANT'S, HARTZ, FIDOPHARM, etc.), but also large AH multinationals like ZOETIS and NOVARTIS have now their own FRONTLINE clone(s). These or other companies have also followed the other option, developing new formulations, e.g. mixing fipronil with active ingredients that MERIAL had not used in its original formulations with fipronil.
But all these companies have numerous options to get their 9.7% fipronil spot-on. They may buy the active ingredient (fipronil) in China or elsewhere (perhaps also from MERIAL, the original product) and manufacture the formulation themselves. Or they may buy finished formulation bulk and pack it themselves. Or the can directly buy the finished product packed and labeled. Several AH-companies may get exactly the same formulation from the same generic manufacturer, or may order a slightly different formulation (e.g. slightly different inert ingredients) from the same manufacturer. To increase confusion, some companies follow a multi-brand strategy using different channel-specific brands for exactly the same product.
A consequence of all this is that there are now dozens of brands available everywhere (vets, pharmacies, supermarkets, pet shops, online, etc.) that are basically the same (e.g. a 9.7% fipronil spot-on for dogs and cats) and nobody knows who has manufactured what and where, i.e. who really stands behind, and what quality can you expect. It may well happen that brand "A" sold by a large highly reputablemultinational is exactly the same as brand "B" sold by a less reputable online shop.
New formulations with generic active ingredients
This is also very frequently done when an active ingredient loses patent protection. In fact, there are some AH companies that are quite strong and innovative doing this (e.g. VIRBAC, NORBROOK) and have introduced interesting formulations with added-value that the original manufacturers had not developed.
Such innovative formulations are often patent-protected as well, but will sooner or later lose protection too and, if they have been successful, they will be copied as well.
Which antiparasitic active ingredients are still patent-protected?
Very few, a small minority. There are about one hundred active ingredients used nowadays in veterinary parasiticides. Those most vastly used are reviewed in this site in the section on active ingredients. Only five are currently patent-protected: four used in dogs and cats againts fleas/ticks (afoxolaner, fluralaner, pyriprole, spinetoram), and one used against gastrointestinal roundworms in sheep (monepantel).
This means that all active ingredients currently used on dogs and cats against worms are generics (i.e. have lost patent protection), and all active ingredients used on livestock against both external (flies, ticks, mites, lice, etc.) and internal (parasitic worms) parasites are also generics, excepting one (monepantel).
All AH-multinationals (BAYER, MERIAL, NOVARTIS, ZOETIS, etc,) traditionally involved in the marketing of antiparasitics have now products in their portfolios that contain generic active ingredients that do not come from their own pipelines, i.e. that were discovered by their historic competitors (see table below). Thirty years ago, when I came to this business, this was exceptional and was considered as highly embarrassing, certainly a weakness. Well, times they are a-changin'...
|Usage of generic active ingredients by AH multinationals (2015)
O = Original company that introduced the active ingredient
O* = Inherited through merger or acquisition
+ = Used by the corresponding company
However, not all original products are copied. The reason is that often only the most popular is copied, or the easiets to handle, or just the first in a class to lose patent protection. Among the macrocyclic lactones, whereas there are thousands of ivermectin generics, there are very few generics from other compounds of this chemical class. (e.g. doramectin, selamectin, milbemycin oxime, etc.). One reason is that ivermectin was the first to lose patent protection, and consequently the first one that became vailable for generic manufacturers. Another reason is that ivermectin is good enough for most indications, although other macrociclc lactones are slightly better against particular parasites or for specific indications.
Unfortunately, many manufacturers of generic antiparasitics that contain only veteran compounds decorate them with stereotypical expressions like "newest technology", "technological break-through", "innovative formulation", and the like, which are not only misleading, but simply bogus.