In the past months and weeks, I had several requests for helping with the registration of varroa treatments in the EU. And I noticed – again – that there are a few misunderstandings about the process. Hearing these quite often, here are the very basics of the procedure. The things you should know from the very beginning.
Let’s get the most important thing out of the way first: Varroa treatments are veterinary medicine. This means that the have to prove that they kill varroa mites (efficacy), but not the bees (safety for the treated animal). And they don’t create problems for the user (i.e. beekeeper) or the consumer (while eating honey, mostly).
But it’s natural!
This special circumstance – being a medicinal product, a drug – means that varroa treatments have to be registered. This is already a surprise for some. Especially, when the product in question is “natural”. This word is becoming a pet peeve of mine. “Natural” doesn’t mean safe or harmless automatically. Some of the most potent venoms come from plants or animals. It’s totally “natural” to get bit by a cobra. Nonetheless, when that happens, go and get an antidote as soon as possible!
So, what do people mean when they say “natural”? Usually, that the active substance is of natural origin. The active substance is the ingredient of the varroa treatment that kills the mite. I explained that in the first post of my varroa series. “Of natural origin” means that you could find that substance somewhere in nature, though for pharmaceutical purposes it’s usually synthesized in a lab, too. And even if you extract them from plants, they’re chemicals. Even water is a chemical. Honey is a mixture of many chemicals. “Natural” or “chemical” aren’t categories that help in this context.
However, as I said, even substances like that can be harmful, too. It’s the dose that makes the poison, as Paracelsus said. So, even with “natural” substances, it’s necessary to make the registration for varroa treatments.
In this context, another very basic rule: Every substance that has an effect, has potential side effects, too. If a product claims to be “100% safe” (or anything else for 100%) run. It’s scam. The question to answer for a medicinal product is different: Do the benefits outweigh the risks enough?
Risk vs. benefits
So, what does that mean? The benefits of a treatment seem clear: It kills varroa mites and, by this, avoids that the colony dies of the parasite. In very poor words. But how much of the mites should a treatment kill? Because also in this case, we never get a 100%, there will always be a few mites that survive the treatment. Because every active substance has pros and cons. The European guideline for varroa treatments sets the minimum efficacy at 90% for substances of natural origin and at 95% for synthetic substances.
This comes from other veterinary guidelines. In beekeeping we’re in the privileged position of having highly efficient organic acids and essential oils. Oxalic acid outcompetes all the other substances when looking at the efficacy – when used correctly, obviously.
When we talk about risks, on the other hand, it’s about the effects on the honey bee colony. So, in clinical studies, we also check if the treatment affects bee health. These are the things meant with “side effects”, e.g. killing the queen or brood, high worker mortality, or changes of behaviour. If these side effects are frequent (i.e. more than a few percent of the cases), then even the best efficacy won’t be enough to convince authorities to register this treatment. It may get an emergency treatment, in case nothing else helps. An example of this may be the emergency registration of fumagillin against Nosema ceranae. But varroa? Nothing I knew of in the beekeeping world.
Quality of the product
What I described previously is the clinical part of the registration of varroa treatments. The part I’m most involved with. It’s also the part that gets most questions and objections from authorities during the process. But there are also other aspects that have to examined before an authorisation for the European market. Especially the quality of the product is another tricky one. For drugs, there are special requirements on that – again to make sure that the benefits are larger than the risks of a treatment.
For instance, the stability of the product is important. It has to make sure that the active substance is available at the same concentration or dose over a period of two years. Within this period, the product should be the same as immediately after production. If the active substance or any other ingredient degrades in this period, it should be proven that this doesn’t affect efficacy or safety.
Also the manufacturing process should be always the same, und “Good Manufacturing Practices”. During that process, something could go wrong and then it should be documented which batch is affected and which step has to be fixed.
Data package for registration of varroa treatments in the EU
These two parts – the clinics and the quality – are the two which get most objections and questions from the authorities during the authorisation process. But there’s even more. If you want to register a varroa treatment in the EU, you need a dossier with these four parts:
Part 1 gives all the administrative information, description of the final presentation of the product, including packaging, labelling and package leaflet. So, who’s responsible for this product, how will it be sold, and how do you explain how to use it.
Part 2 specifies the quality of the product, as described above. In Part 3, we get the risks to humans and the environment. So, are there residues of the treatment in the honey? What safety measures should the beekeeper use during the treatment? What do you do with the used product after the end of the treatment?
And finally, Part 4. The pre-clinical and clinical trials. In addition to the efficacy and safety for the treated animal, this includes also dose-finding studies, how to use the product, and what to do to avoid resistance.
This dossier, obviously, should be based on data, on studies done BEFORE the dossier is written and submitted. And before putting together the dossier, it’s important to check if the data are complete and meet the requirements of the EU. This sometimes generates incomprehension from applicants from outside the EU. And they try with incomplete information. Followed by losing money because you pay the fees not for the successful registration, but for the process itself. As it happened with HopGuard, for instance. It’s registered in the US, but not in the EU because of major concerns on efficacy, safety, and quality of the product.
Another misunderstanding during registration of varroa treatments
Honey bees are classified as “minor species” in the veterinary world. This is because of the smaller market than for, let’s say, cattle or pigs. In consequence, the fees for the registration of varroa treatments are lower. But “minor species” doesn’t mean that the rules aren’t applied as strictly as with “major species”.
The steps to go are always the same. If you want to submit a dossier at a certain time for whatever reason, then you have to calculate the necessary lead times to have the dossier ready at that date. It doesn’t make sense to think “OK, we submit because we’re so confident that our product is fantastic!”. It may be the case, but if the data don’t document this enough, you won’t get the registration and marketing authorisation.
Rules like this exist all over the world. From the cases I’ve assisted for dossiers the requirements are similar. The EU has the reputation of being very restrictive. Maybe. The approach here is to “avoid risks”, not of “taking possible benefits”. There has to be a balance. Both approaches have pros and cons. But if you want to sell a varroa treatment in the EU, you’ll have to follow the rules. As European manufacturers have to follow US rules if they want to register there (or wherever else in the world). That’s how it goes. And if you want to change the rules, it has to be based on data. Not on believe systems. Because, again, we’re talking about veterinary medicine.
