The cascade and the SPC: how vets are sometimes caught between a rock and a hard place
The Cascade and the SPC: how vets are sometimes caught between a rock and a hard place
Potentially the most misunderstood, certainly one of the most disliked, bits of legislation that affect the work of a practising vet is that surrounding the licensing of medicines and in particular, “The Cascade”. Yet it was originally introduced to help ease the restrictions on medicines use in animals.
The evolution of animal medicines legislation
The cascade first appeared in response to a new EU regulation (one I should add, the UK contributed to) covering animal medicines. At its simplest the law stated that any medicine used for animals had to be licensed for that animal and manufactured to agreed standards. It seems remarkable that, up until the early 1990s, the approach to the use of medicines in animals was a little lax. To be fair, in the absence of specific medicines, vets had little alternative to adaptation from human medicine for many years. However, it also has to be acknowledged that many practices continued using the cheaper human generics even when authorised veterinary medicines were available, particularly oral medicines for small animals. Which is curious when you consider it, for no doctor would prescribe an animal medicine for a human.
As the licensing process requires data and an application, this incurred a not insignificant cost, so the prices of the veterinary licensed medicines rose. Examples such as amoxicilin and phenobarbital are some that stick in the mind as once cheap, but then became more expensive products. The veterinary press (for it was before the age of the keyboard protest) was full of letters predicting dire consequences for animal welfare because of the price increase. Not least of these was animals being euthanised because of the cost. From memory, I’m not aware of any such tragic instances.
At around the same time, additional legislation to improve food safety by having fully determined Maximum Residue Levels – used to calculate withdrawal times - was introduced. Initially this was the UK Food Safety Act, but it was superseded by 2000 with the EU directive that no product could be given to food-producing animals unless it had a stated Maximum Residue Level. By this time there was an almost comic number of Acts, Regulations, Statutory Instruments, and Directives relating to animal medicines and so, in 2005, the Veterinary Medical Regulations (VMR) were introduced, which were updated annually up until 2013. (My apologies if some of the above history is not absolutely accurate, but there is a limit to the pleasure derived from trawling legislative archives).
There was a problem though, for however sensible and well-intentioned the varied legislation was, it underestimated the use of medicines in companion animals or competition and pleasure horses and, in particular, the use of medicines in exotic pets or rare conditions, for which the market was too small to justify licensing the product. And so, “The Cascade” was introduced. The earliest specific reference that I have found is in The Medicines (Restrictions on the Administration of Veterinary Medicinal Products) Regulations 1994. Older readers will recall the MAVIS bulletins, and there is mention of, “the cascade” in the October 1994 edition. (There was a trend to be clever with acronyms then, MAVIS was the Medicines Act Veterinary Information Service. She had a sister, AMELIA, whose derivation I cannot find, but evidently someone was having fun at the VMD).
Working with the cascade in practice
Since its introduction, the Cascade has changed little in its wording. One of the commonest phrases in connection with the cascade is that the use of a certain drug is, “against the cascade”. Without wishing to be too pedantic, this is incorrect as a vet can only use a medicine in accordance with the Summary of Product Characteristics (SPC – the old Data Sheet) or failing that, the cascade. The VMR 2013 states that a vet has to use a product that is licensed for the species and the condition. If no product is licensed for species, condition, or both, one can be given outwith the indications of the SPC. The cascade is essentially a guide to the preferred order of unauthorised products or unauthorised applications of products. The pathway is mostly logical, starting with a product licensed for the same species or the same condition in a different species. This makes sense: most mammals handle medicines in similar ways and the pathology of most diseases is similar enough that there is a good probability of the product working and being safe for the patient. The next step is to use human products, or products from another country. I struggle with this, for, logically, if a product has been developed for use for a condition in a particular species, it makes more sense to use that rather than using a human product. This seems to be one of those occasions when harmonisation didn’t work to best advantage. Sadly, those in power who control international boundaries are not noted for being scientists and we are stuck with it. The last step of the cascade is the use of specially-prepared medicines. For food-producing animals, any product used must be listed in the Table of Allowed Substances (EC 37/2010). Products from other member states can be used, but not human medicines, as these have no MRL data.
“Off-label” use of medicines
The terms “off label” and “within the cascade” are often interchanged and confused, although there is little difference in their application in practice. In truth, there is no legal definition of “off-label,” and the VMD’s guidance refers only to “authorised use” and “cascade use”. The VMD gives good examplex of what is “authorised” and what is “cascade” use in its online guidance on the use of the Cascade. In essence anything that is not, “authorised” is used under the cascade. It does get a tad pedantic and a specific example can be used to illustrate the difference. The L4 vaccine (MSD and Virbac) has an authorised interval of 4 weeks, which, according to the manufacturers, is the period used in the trial data. The interval is more specific than most vaccines, which usually give a range, say 2 to 4 weeks. Administering the second dose at anything other than 4 weeks is therefore unauthorised use. However, the cascade permits the use in this manner, because there is no other product that is available to use at any other interval. If this seems unnecessarily bureaucratic, that’s because it is. In addition, our professional code of conduct recommends that a consent form be signed for this unauthorised use. One has got used to the bemused looks from human health professionals at the knots we seem to have tied for ourselves.
Prescribing – a criminal act?
It’s a curiosity (and a profound annoyance) that the VMR (2013) makes it an offence to be in breach of section 8 (Administration of the product) of the regulations (i.e. that a product administered to an animal must have, and be administered in accordance with, a marketing authorisation; or be administered in accordance with the cascade or be a product from small pet animals exempt from needing an authorisation). While the cascade does provide a sort of escape clause, this places undue pressure on the prescribing vet, should an error occur. The bewilderment of medical practitioners is increased when they learn this, for no such restriction applies to them and in many cases (such as chemotherapy) it would severely restrict their pharmacopoeia. The problems caused by the writing of the VMR is unfortunately exacerbated by the writing of the SPCs
Summary of Product Characteristics - a pedant’s delight.
While the SPC is a source of useful information, it can create some significant problems for practising vets, especially where contraindications are concerned. One example is that of meloxicam (all suppliers) which has the specific contraindication, “Do not use in pregnant or lactating animals.” In reality, this means it has not been tested in these animals (and one can understand why, given the ethical considerations or the testing regime). However, it presents the practitioner with a dilemma with a canine caesarean section, because the, “Do not use…” phrase implies there is a reason not to use the product. From speaking to the manufacturers, there is reasonable evidence to support the use, especially as meloxicam is licensed for use in pregnant and lactating cattle. So why is a phrase that has no evidence to support it permitted in the legal document that accompanies the product? It is interesting that the European Medicines Agency guidelines for human SPCs states, “Lack of data alone should not lead to a contraindication.” I can find no similar guidelines for the construction of veterinary SPCs and I’m given to wonder if this phrase is not purely of the VMD’s whim. At the time of writing I am awaiting a response from the VMD itself.
A “Do not use” contraindication presents a vet with some difficulties should a complaint arise (negligence or professional conduct). For while the use of meloxicam can be justified in scientific terms, it is much harder for a vet to defend themselves against a specific, “Do not use”, contraindication. A simple solution is to use the phrase, “The efficacy and safety of this product in pregnant and lactating animals has not been tested”, and in fairness this phrase does seem to be becoming more common in SPCs.
Another oddity that “forces” the vet into using the cascade and having to justify a breach of the VMR relates again to poor wording on the SPC. Tetracycline sprays are an effective treatment for footrot in sheep. However most of the cans carry instructions to pare the hoof as part of the administration. Following some extensive research, I have found that hoof-paring is now no longer recommended as part of footrot treatment. The SPC thus has advice in a legal document that is contrary to scientific opinion. I understand that to change such advice is a variation to a licence and as such attracts a fee, so it is understandable that manufacturers are reluctant to make changes unless they have to. I feel however that this is not an additional use, but a change in understanding, and the incorrect advice should be removed without a fee, not least as it applies to more than one manufacturer.
As vets we need confidence that the products we use are manufactured to a set standard, that they work, that any side-effects or contraindications are recorded, and that food safety from residues is assured. That has been the achievement of the changes to veterinary medicines legislation and it is to be welcomed. And for all of the problem examples outlined above, the cascade remains a sensible part of veterinary prescribing, allowing treatment of animals where the costs of licensing outweigh the potential sales. While I, and many vets would like to see the law change so that we no longer have to justify why we are breaking the law, much of the problems this creates could be achieve by changing the requirements for the SPC. The Summary of Product Characteristics should be a guide to the use of a product and not be a list of legally constraining, frequently inflexible instructions. Especially if those instructions are without foundation.
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