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U.S. Department of Health and Human Services

Animal & Veterinary

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MUMS - Australian Perspective

Dr. Philip Reeves

DR. REEVES:  Thanks, Dr. Craigmill, and good morning, ladies and gentlemen.  I had the good fortune of dropping into Dr. Craigmill’s laboratory on the way across. It’s something like a 14-hour flight, and I stopped off and I was pleased I did; I thought I was back in Australia.  When I walked into Dr. Craigmill’s office.  He has posters of Australian wildlife all around the office.  We looked at some PDPK, population PK and meta-analysis and the minor-use laboratories, and so forth, so I was very thankful for that.
Before presenting the Australian perspective, I would like to thank the workshop organizers for inviting me to participate.  This has been a wonderful opportunity to learn a lot of good -- you know, the good progress that has been going on, and also about the future direction for making animal drugs available for MUMS.  In my presentation, first I will provide you with a brief overview of the regulatory framework that applies to drug approvals for MUMS in Australia.  Second, I will discuss very briefly the situation in Australia relating to MUMS.

The National Registration Scheme for agricultural chemicals and animal drugs in Australia is a partnership between the Australian government and the State and Territory governments.  The APVMA is the regulatory agency that administers National Registration Scheme.  The APVMA, in conjunction with various other government agencies, is also responsible for conducting technical assessments of registration data and for registering veterinary medicines.  The States and Territory governments are responsible for the control of use activities.  The information submitted to the APVMA in support of registration applications must establish that the veterinary medicines meet the criteria shown on the slide.  They must be safe to the target species, users, consumers, and the environment.  They must be efficacious, suitably formulated and labeled; and they must no unduly prejudice trade.  Australia is a little different in this regard since trade is one of our legislative criteria, and we have to be satisfied on trade grounds before we register with product.

The regulation of animal drugs for MUMS in Australia provides two approval options.  In addition, provisions exist in control-of-use legislation which I will describe later.  The two options are actually shown there.  The first is full registration, which can lead to marketing.  The second is a minor use permit, which does not lead to marketing.  In both cases, applications are made to APVMA.

With the first option, full registration, it requires the data submitted by the applicant satisfy the APVMA on the grounds of product quality, efficacy and safety.  There are 10 areas as shown here the data need to address.  In some instances, overseas data and/or assessment reports may be submitted and may be all that is required to obtain full registration. 

The second option is that of the minor use permit.   The APVMA has a minor use program in place, which is underpinned by minor use permits.  Data on safety to humans, target species, the environment and also efficacy are required to support an application for a minor use permit, and in that regard there is no difference in the criteria that have to be met, whether it is full registration or a minor use permit.  Importantly, a minor use permit may be considered by the APVMA in circumstances where a full data set is not available.  Conditions are then included on the permit to ensure that the necessary criteria are satisfied.
Either manufacturers or relevant producers can make application to APVMA for minor use permits, and incentives are in place to encourage producer groups to apply for minor use permits.  The first incentive is that an application received from producers or from government are exempt from fees; and, secondly, the time frame for completing the assessment and issuing a permit is commonly three months.  However that really depends on the complexity of the application.  As I said earlier, this does not lead to marketing.  It does not appear on the product label.  Rather, it is a means of making drugs available to minor use industries.

As I indicated earlier, control of use activities are the responsibility of the State and Territory governments; the APVMA has no activity in relation to control-of-use.  The key components of control of use legislation that relate to drug approvals for MUMS is shown here.  Off-label use in minor food-producing species is permitted; However, such use is restricted to veterinarians in at least a couple of States and a couple of Territories within Australia.  Additional conditions apply.  For example, it is an offense for anybody to use drugs contrary to a restraint statement on a label. The exception to that is veterinarians can actually use an animal drug that was designed for herd treatment on a single animal treatment.  It is also an offence for anyone, including veterinarians, to use an animal drug contrary to a "do not" statement.  I will pass over point four for the time being and come back to it on the next slide; and, finally, it is an offence to cause violative residues in animal products.  

Australia has learned to manage residues of veterinary drugs in foods very well, because it relies so heavily on exports of agricultural commodities.  For example, 70 or 80 percent of some animal commodities such as beef is exported.

Veterinarians’ prescribing rights fall out of the control-of-use legislation that we looked at on the previous slide.  Veterinarians’ prescribing rights facilitate off-label use.  Both the APVMA and the State and Territory governments have provisions in legislation for prescribing rights.  The rights may not extend to food-producing animals in every State and Territory.  It is a little bit like the CVM versus EPA I guess.  It depends on what legislation animal drugs fall under.  For example, external parasiticides that are applied externally to an animal come under Pesticides legislation in certain states.  In that case, veterinarians’ prescribing rights do not apply because it is the wrong legislation.  

Moving to the third point, veterinarians can use, prescribe, supply, and recommend the use of veterinary medicines contrary to a label instruction to animals under their care.  However, a valid veterinarian-client-patient relationship must exist, a diagnosis must have been made, and there must be no currently marketed drugs available to treat that particular disease.  Finally, the recommended dose may have been shown to be ineffective for the registered product.  Then that is another situation where veterinarians’ prescribing rights apply.

`  In relation to minor species, it is important to note that veterinary surgeons can use animal drugs that are registered for use on minor species contrary to label instructions for minor species.  In addition, veterinary surgeons can use unregistered veterinary medicines on minor species.  Finally, veterinarians are obligated to provide full and appropriate written instructions about the treatment of an animal under their care, which go to the person in charge of the animal at the time of treatment.

The second part of my talk will look at some of the minor uses and the efforts that Australia has gone to in certain areas.  This slide breaks the MUMS into minor uses in major species and minor species.  In terms of minor uses in major species, dairy heifers and replacement pullets for egg production and dairy sheep would be another, are examples of minor uses in major species which are important.  I will come back to those on the next slide.

In terms of minor species, they are listed there, and I guess three of those, in agriculture species, honey bees and goats, are probably the most important and the most work has been done on those.  I will discuss those a little bit. 

To touch first on minor uses in major species, the difficulty relating to drug approvals for dairy heifers and replacement pullets for egg production are described here.  The first point reads, “many veterinary chemical products currently registered for use in either cattle or poultry carry a label restraint prohibiting their use in cattle and poultry that are now producing, or may in the future produce, milk or eggs for human consumption.”  In the interest of time I will restrict my comments to dairy heifers, and I won’t talk about replacement pullets.  

You can see from the first statement that the problem for us is actually created by what -- the phrase that sits between the two commas, which is "or may in the future produce".  Basically the objective of this statement in the first instance --- from residue evaluations, and what we were endeavoring to do was protect residues in milk from either lactating cows or during the non-lactational period just prior to the commencement of lactation. 

That is all very well, but what we have done with that extra phrase in there is trap all those heifers between the age of, well, birth and 18 months or whenever they might produce their first calf.  Basically what that does, it prevents a lot of drugs that would otherwise be fit for use on these young heifers from being used.  For example, some of the animal drugs that are used on beef cattle, for example, may well be suitable for use an replacement heifers.  

We can take an actual example to demonstrate this, the imidocarb as we have heard already is an antiprotozoal indicated for preventing and treating babesiosis and treating anaplasma in cattle.  Basically cattle tick are very common in Australia, as is tick fever or red water as we call it, and in endemic areas calves acquire babesia infection at a young age.  They become immune to the clinical disease and then act as carriers of the infection.  Without constant reinfection, immunity is lost within several months and the clinical disease results.  If that particular dairy heifer is treated with imidocarb, which happens to carry this particular restraint statement, it means that that dairy heifer can never enter the milking herd.  That is a major problem for us, and it is something that we are addressing at the present time.  I would certainly be pleased to hear how other regulatory agencies are handling that matter.

In terms of minor species, I will just touch on the efforts that Australia has gone to up to this point with respect to the agricultural species, honey bees, and goats.

I will start with aquaculture.  Today aquaculture is an established industry throughout Australia, and while there is over 40 species in commercial production, five main species account for about 85 percent of production.  These are tuna, pearls, salmon, oysters, and prawns.  The industry is growing rapidly, as I think it is in many countries around the world.  We are showing average increases in growth of about 13 percent per annum, and estimates, projections, is that the industry is going to be worth about $2.5-billion annually by 2010.  In fact, that projection was made in 1990, and the figure is actually running ahead of that projection, so it is doing very well.  

What I will do is give you a thumbnail sketch of the strategy that has been adopted in Australia to address the drug needs for the industry.  In 1995, an industry survey was conducted to identify and to prioritize industry’s needs for veterinary drugs.  In 1996, the Australian government funded a project with the aim of providing access to at least representative drugs in the major categories that were identified in the industry survey.  The result was that of 12 drugs targeted, 10 were made available.  Most of those were by the minor use permit, and a couple of them by full registration.  

In 2000, the Australian government then funded a second project to put in place a system to assemble and generate the required information to apply for minor use permits, but it had to make the requirements of the industry itself, the industry-driven priorities.  Now when I talk about funding from government, I am not talking about funding of research.  Rather it is funding of all sorts of administrative type procedures.  Paying for a consultant for example to get onboard to take care of this and to take care of ---.  The funding for this came from the producer groups. 

As a result of the 2000 project, a company was contracted to establish and maintain approvals for use of veterinary drugs under the minor use program.  This was an extremely successful arrangement.  Unfortunately, the particular company went out of business in 2003 and it ceased operations.  I guess I should point out that -- I have already, but I will say it again.  We don’t put minor use approvals on label, and it was very important that there was some process in place for actually renewing these minor use permits.  Lots of the producer groups didn’t have the incentive to do that, and so they would often take a minor use permit but then let it lapse; and we were relying very heavily on this particular company to keep them moving and also to consolidate and to make other people, other producers within the industry, know that they existed, that there was no need to apply a second time.

In 2002, the Australian honey production was estimated to be worth $50-million.  Of that, something like $20-million was exported.  So it is a very small industry.  I think it ranged about -- well, it did range fourth in the world in terms of export.  I am not sure if it is still fourth.  

The main diseases or pests for which drugs are approved are European foulbrood disease and the varroa mite.  However, I must stress the varroa mite does not occur in Australia.  It does occur in countries to our north.  So what we have done is make drugs available under a contingency permit should they be needed one day in case that particular disease enters Australia.  

European foulbrood disease caused by Melissococcus pluton is endemic in all Australian states except Western Australia, and the impact of the disease necessitated the introduction of oxytetracycline treatment in 1977.  This antibiotic can be administered to broad boxes as either dry treatment in powdered sugar as we saw previously, or as wet treatment in syrup.  We conducted some residue trials, or at the producers conducted the residue trials.  They were able to show that the residue levels were something like five-fold higher following we treatment compared to “dry treatment.”  As a result, Australia phased out “wet treatment” to ensure that residues did not reach such high levels.  We also put in place a temporary MRL for oxytetracycline in honey.  During this time residue data have been generated so that we can revisit that and produce a permanent MRL.

The Australian goat industry is the world’s largest exporter of goat meat, and recently the industry conducted a survey into drug approvals and its needs.  Those animals -- sorry.  Those animal drugs and pesticides that were prioritized by the industry are shown here.  I have simply categorized them into those drugs and pesticides that are already registered and those for which there are no registered uses.  The industry is now pursuing this and working with interested parties to try and get drugs approved for this by the industry.  Thank you.

  DR. CRAIGMILL:  Thanks very much, Phil.  Are there any housekeeping issues at this time?
  VOICE:  Just come back on time.

DR. CRAIGMILL:  Just come back.  We will begin again at 1:15.  I would like to thank all of the speakers this morning for their excellent presentations and for getting this workshop off to an outstanding beginning.  As one of the two, three, four organizers, I am very happy with what we have accomplished so far.  I would also like to recognize the excellent assistance that we received from Aleda Sindalar, from Kandi Crosier outside, Sandy Ogletree and Carolyn Whitford who helped us all work this up.
  (A luncheon break was taken at 12:00 p.m.)

A F T E R N O O N   S E S S I O N
 (1:15 p.m.)

DR. WEBB:  Housekeeping again.  Parking, you don’t have to pay.  Show them your badge when you leave.  If you don’t have a badge or you have lost it, there are code numbers in the back that will get you life parking here forever free.
  DR. WEBB:  And we will pass back to Dr. Sundlof for the next introduction.

DR. SUNDLOF:  Thank you, Dr. Webb.  It is my pleasure now to introduce Dr. Steve Groft.  One of the nice things about this is that most of us, and I think all of us probably, are very much novices as we approach the issue of actual regulation of orphan products for animals.  But Dr. Groft has had much experience in this area, and in fact was at one time with the FDA Office of Orphan Drugs.  He is a pharm D.  He is the Director of the Office of Rare Diseases at the National Institutes of Health, and he has -- just in my brief talking with him, he has been in the Indian Health Service and mentioned the FDA, and now with the NIH, but all within the Department of Health and Human Services I am proud to say.  So thank you, Steve, and I am looking forward to your talk.