The big question is the number of in vivo studies required to show efficacy

Posted 8 January, 2018

Efficacy is the main talking point as the EU Commission (EC) revises the EU feed additives regulation, says an expert.

That legislation (Regulation (EC) No 1831/2003) has not undergone an evaluation since its entry into force in October 2003. 

Elinor McCartney, president of food chain consultancy group, Pen & Tec, weighed in some of the outstanding issues for us.

While there are some positives to be drawn from the process so far, she told us there has been a somewhat disjointed approach from the European Safety Authority (EFSA) and the Commission in relation to this regulatory face-lift.

“There has been a sort of disconnect in what the Commission said they were going to do in the Evaluation Roadmap and what they have actually done. The Commission, originally, said it was going to open a public consultation for the last quarter of 2017 for a duration of three months. However, it instead opened up the publication consultation from 28 August to 25 September, a move which meant Pen & Tec, for example, and perhaps other stakeholders as well, were taken by surprise and did not have a lot of time to prepare their feedback.”

Another main concern for industry, she said, is that EFSA has already updated practically all key guidance documents in advance of EC evaluation of the feed additive regulation.

The EU risk assessor is keen to ensure that feed additive guidance updates were completed before the renewal of the current FEEDAP panel in June 2018. “Due to a rule change, from that date, many long-standing experts are no longer allowed to serve on that panel, so EFSA, naturally, wanted to leverage existing expertise and get the documents finalized within that period,” she said.

However, she said EFSA guidance documents should not be more demanding than EU legislation. The logical roadmap would have been to first update the regulation and then start updating the EFSA guidance documents:

“There is a kind of feeling among stakeholders, perhaps erroneous, that the Commission does not intend to enter into much detail on this evaluation, that the EC would rather prefer a simple administrative approach, rather than a comprehensive technical review, clause by clause.”

She noted that lack of a detailed evaluation of the feed additive regulation might mean loss of flexibility and hence industry will have to comply strictly with the EFSA guidance documents.

Little discord around safety testing

“By and large, nobody has major problems with EFSA’s approach to safety – there are classic studies on genotoxicity and toxicity that you will have to submit when you want to have EFSA conduct a risk assessment on a completely new molecule – nobody takes issues with that. There are concerns in relation to applying a similar “one-size fits all” approach to the safety assessment of live microorganisms; nevertheless, EFSA would seem to be open to in vitro and WGS (Whole Genome Sequence) approaches there.

“I do think the updated EFSA safety guidance document is quite useful – a step in the right direction. For example, it is no longer necessary to do a standard toxicity test – the 90-day rat oral toxicity study – for an additive if there is sufficient information in the published literature. I also think that, from a safety point of view, EFSA is much more willing to accept that there is no need to do a 90-day rat study on live microorganisms if you have a WGS analysis and you have done your phenotypic testing on antimicrobial resistance and potential toxins and virulence factors.”

Efficacy studies proving to be the sticking point 

Efficacy is one topic that generated many comments during the public consultation of the feed additive regulation, now closed, and will generate many comments on EFSA’s public consultation f efficacy guidance, open until 28 January 2018. Only a few Member States, such as the UK and Belgium, argue it should be left to the market to decide on the efficacy of feed additives.

“The revised EFSA efficacy guidance document is an improvement on what we had before but there is more room for flexibility on the number of in vivo studies required to show efficacy, patriculalry for zootechnical feed additives.”

In her capacity as Food Chain Working Group Secretary of the Association of Veterinary Consultants (AVC), McCartney, along with other EFSA stakeholder experts, supported EFSA in its development of the draft guidance on efficacy.

“I pointed out to EFSA that, under current efficacy guidance for zootechnical feed additives, if you want to have a feed additive approved for all animal species, you would need to produce around 100 in vivo efficacy studies, a process involving many years and enormous costs.

“This is because for a such feed additives you need to do at least three studies in each animal category – broilers, laying hens, turkeys, piglets, pigs, sows, dairy, beef, calves, fin fish, dogs, cats, horses, etc., and in some cases you will have to run additional studies as there will be some studies where you won’t get significant results.”

The AVC and other EFSA stakeholders question the necessity of such a “heavy” approach.

“AVC has suggested that you could reduce the amount of efficacy studies per additive by only requiring industry to do three in vivo studies for the first category – typically, that would be broilers as they are the easiest to run trials with – and then, ask industry to run only one in vivo study for each additional animal category. Then you could see a decrease from around 75 to 100 studies to around 15 studies, a significant reduction.”

She said EFSA’s revised guidance document has allowed for some flexibility but not to the degree that stakeholders had requested. “I think there is some scope there for the Commission to step in and say it agrees there could be more flexibility. However, it would be important to write that into the new regulation, as if is not written into the law then industry will have to adhere to EFSA guidance.”

There is an opportunity to be more flexible without jeopardizing safety, she said.

McCartney said the AVC and other stakeholder experts have pointed out, and EFSA has accepted, that there is no feed additive that will work 100% of the time in all the situations an animal will encounter.

“Therefore, once you have basic proof of concept for one animal category – with three in vivo studies – together with some evidence of efficacy in the shape of one in vivo study in each additional category – that should be enough.”

Another industry suggestion is to make much more use of in vitro and ex vivo studies especially in the case of live microorganisms. In vitro models that simulate the gut can show the live microorganism has the potential to suppress Salmonella and other pathogenic bacteria, said the regulatory consultant.

Holder-specific approvals

An aspect of concern that stakeholders such as DSM also highlighted to the EC is the fact that innovative additives are not holder-specific under the existing regulation, a view with which McCartney concurs.

“I think feed additive consortiums are being unfairly treated because they do all the work and then the approvals are generic. Afterwards, any company can come along, they have done no work at all and, yet, they can put their products on the market provided they meet the specifications in the regulation.

“What should happen is that the initial authorization should be given to the original single applicant or multiple applicants; then other companies that come along later should have to pay, and in that way they share in the costs involved in securing that original approval.”

If industry cannot get a good return on investment, then companies will be reluctant to invest in innovation, she warned.

The Commission always says no it has to be like this to support SMEs that don’t have the budget. However, we have many SME clients and these are some of the most innovative companies around, and we see that they are willing to invest, but they need the EC to protect their investment – more can be done, and holder-specific approvals is an excellent way to protect and stimulate innovation, particularly important as we seek alternatives to veterinary antibiotics.”

Unfair practice and market distortion

FEFANA stakeholders also pointed out another ‘market distorting’ issue in feedback to the Commission, namely that the difference between feed additives and feed materials is not defined precisely enough in the respective pieces of legislation. Though the two regulations specifically exclude feed materials from feed additives – a feed material cannot be a feed additive, the legislations allows for similar claims for both feeds and feed additives. In that way, the legislator has unintentionally created an unfair market place and market imbalance.

McCartney agreed with FEFANA stakeholders on this:

“You can effectively make the same or similar physiological and nutritional claims on a feed material that you can make on a feed additive and this creates a market distortion. For an additive, you have to demonstrate efficacy via EFSA but for a feed material you can make a claim based on much “softer” data, on information extrapolated from published studies, for example, or from in-house studies, which in my experience are not subject to the same evaluation rigor as an additive that is examined by EFSA.”

Continuing on that point, she noted a lack of harmonization across the food chain in that, under the nutrition and health claims regulation, a company can no longer make any claim on a food where efficacy has not been demonstrated to EFSA’s satisfaction. As an example, a feed company can make a claim on turmeric, which is a dried spice classified as a feed material, if it has data to support the claim. A typical turmeric claim would be “keeps joints supple”. There is no pre-market requirement to produce an EFSA dossier for a feed containing turmeric with such a claim but any health claim on turmeric as a food requires an EFSA assessment prior to making such a claim to consumers.

“I think there is a lot of scope for more harmonization across the various food chain regulations from nutritional and health claims to pesticides to feed additives to biocides.”

Open to innovation

McCartney stressed, though, that the EU Commission is, in fact, more open to innovation today in terms of food and feed applications than it has been in the past.

“Take nisin, for example, an antibacterial peptide that can prevent undesirable bacterial growth, but is not an antibiotic.

“I remember asking the Commission, around 10 years ago, if nisin, since it was authorized for use in food, could be used in feed and they said no back then. I think nowadays the regulator is much more open to innovative applications if the products can be justified as non-antibiotic and can help animals perform better and therefore contribute to a reduction in the use of antibiotics.”

And both the Commission and EFSA would seem to have an appetite for establishing new categories of feed additives, said McCartney.

There have been repeated calls for a new functional group of feed additives in the regulation that would create a stimulus for the development and registration of products that support the physiological functions of animals in good health, and that can improve welfare and performance and would further reduce the need for antibiotics.

“Healthy layers, broilers and dairy cows are subject to many challenges, driven by modern genetic performance potential, and in the course of their lives are exposed to non-infectious diseases, environmental and production conditions that are quite stressful. New products like probiotics or some botanicals will actually help healthy animals to overcome bumps in the road in their growth and development. There are many new products in the pipeline, still under development, that will help ameliorate those challenges and support animal health while reducing antibiotics in animal production.”

In ovo feeding

Many companies would also like to have a clearer mandate on new technology such as in ovo nutrition, said McCartney. For that, they require a clear acceptance from regulators that this innovation is welcome. In ovo feeding is applied to the amniotic fluid of eggs at 18 days incubation, and may involve key nutrients and additives such as amino acids, nucleotides, trace minerals, enzymes or probiotics. Data from in ovo nutrition and spray-gel feeding of newly-hatched chicks show that such innovative practices can help reduce antibiotic use in the first few days of a chick’s life, as well as achieving significant reductions in early bird mortality related to dehydration and starvation, she said.

“To encourage more innovation in this area and to give Member States and the Commission the confidence that this is a safe way to apply feed additives, safety evaluation of in ovo and post-hatch feeding by EFSA is needed.”

It is up to the stakeholders, though, to press this home with the Commission, so that, for example, in ovo feeding is included in the revamped rules as a legitimate way of administering additives, she said.

Otherwise, it might be overlooked. However, I expect the EU Commission would prefer to address that technology outside of the feed additives regulation, perhaps as a simple mandate to EFSA.”

Source: Feed Navigator