MUMS - African Perspective

Dr. Eric Mitema

DR. MITEMA:  Thank you very much.  I would like to thank the organizers for inviting me over and to be able to share some experience with you.  I know it is quite an interesting thing being here, you know, in Rockville.  So it is nice to be part of this meeting and to be able to share some experience and be able to compare some notes.  But as you say most of the regulations in our country, there may be a little difference, but in this workshop I will use Kenya as a case study for Africa, and most of the things that take place in Kenya are fairly the same. 
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We use the drugs just to, you know, take care of some of our animal diseases, and also we can use them as an aid, and their regulation is done by Pharmacy and Poison Board of Kenya.  In today’s talk my main objective is to review some of the scientific requirements for MUMS and also to enlighten some current concerns about these compounds.  For example risk analyses and the risk of use in animal products and also antimicrobial resistence. 
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Now I would like to -- this is more interesting.  I would like to define what I mean by minor species in our terms so you get me right.  The minor species depends where you are, even within Africa.  If you are from north, northeast and the north part of Africa, I list there the camel as a minor species.  But if you are in Egypt or you are in Saudi Arabia, or you are in Somalia and certain parts of north Kenya, the camel would be considered as a major species, because there it is very, very common.  That goes all the way up to the Middle East.  So in terms of Kenya, the minor species includes camels, rabbits, bees, and of course donkeys.  Now the major species includes cattle, sheep, goats, pigs, poultry.  There is also dogs, cats, and horses to some extent, because the horse industry is not very advanced, but those would constitute the major species. 

There, as I say, you see that the goat is also very, very popular in most parts of Africa.  Again, if you look at the northern part of Africa, which is a desert there are somehow that the drier parts, the goat becomes a very, very important animal species because the goats are very hardy.  They can survive everywhere.  They can literally live anywhere and just nibble and just survive, and by nature they have been able to survive that region.  That also extends to up the Middle East.

Now we also have the exotic animals.  Some of you are very familiar with game ranching.  Here we put a little game ranching.  Now we got the big game ranching.  We have got the eland.  We have got the wildebeest.  We got the zebras.  Some of these animals are herbivorous, and we have a problem whereby they have cropped.  Some farmers really have certain big ranches.  They can be able to have these game animals within the ranches, and the government gives them the license to keep these animals.  The animals don’t belong to them, but once they are fenced within their boundary the government gives them the authority, and then the government can give licenses as well where these animals can be cropped at certain time intervals.  So we also call them game ranchers, but nonetheless these animals can only be slaughtered at specified outlets, and also the meat can only be sold in specified restaurants.  So you have to go to a very, very affluent restaurant to be able to be treated to game meat, and you pay dearly for it because of the risk of cutting it and, you know, trying to get it and even treating it.  It is not easy. 

Now we also have the crocodiles.  We have one big crocodile farm near Mombasa.  Probably maybe 2,000 animals, or 2- to 3,000, and crocodile meat is quite a delicacy.  It is a taste between chicken and fish.
  (Laughter.)

I always make a joke to my wife and say, "Look, I’ll eat the crocodile before it gets me, because it is not staying."  Then the ostrich farming is also becoming very, very popular. 

As you know, the BSE and the cholesterol.  We have got about four big ostrich farms, and also that also extends even in South Africa.  So we have a lot of ostrich farms, and the ostrich meat is kind of like a red meat, but very low cholesterol.  So it has been getting a lot of popularity.  

So we have these animals, and most of the time the drugs that are used, you know, we use off label.  Now, when we talk about the minor uses, now this is very tricky as for every country.  What Americans would call minor uses would be major uses in our case, and I’ve given very good examples here.  Now we have three let’s say East Coast Fever theileriosis, then tick fever babesiosis, anaplamosis.  All those are protozoic diseases.  Those diseases could be considered minor.  I know you have Red Water in Texas, the southern part of Texas near El Paso, and maybe anaplamosis near down the southern part of Texas, but in our region these are really major diseases.  So whereas Americans may want approved imidocarb as a minor use, in our case we consider it as a major use.  So I will come back to that as I proceed.  The next slide will probably show a little bit more of that.
  DR. MITEMA:  Oh.  Thank you.
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Now, again, I have some specific treatments which you can consider.  You may consider them as minor.  Now in your context we have theileriosis, which is East Coast Fever.  We have at least three drugs that have been approved for use, and these include parvaquone, buparquone; and then for babesiosis, which is a tick fever in dogs or Red Water in Texas or whatever -- I mean Red Water in cattle, we have diminazene.  Also we have imidocarb.  All those have been approved.  Some of these products also have been reviewed even at the National level.  Then you have anaplasmosis.  We have imidocarb and also we can use tetracyclines as indications for these conditions.

Now as far as Kenya is concerned or our country is concerned, the data requirements, these will comply to CAP 344 of the Pharmacy and Poisons Board which was established as a law in ‘82.  So all drugs in Kenya have to be registered if they are intended for either food animals or companion animals.  The law has been there since 24 years ago, and any product that claims that it has got a therapeutic claim either in livestock or in companion animals must be registered.  Data requirements are basically the same for all drugs, whether it is for minor use or for minor species.  The only difference in the case is if the drug is orphan, which you can borrow that from the human term, but we also have that.  If the condition is such that we see very little of it, the drug can be approved fast because the cost involved in the review and the condition of data may not warrant it, and therefore there is also a waiver of fee as far as that is concerned.
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Now regulation of drugs for MUMS drugs, one of the conditions, one of the aims, just like any other country, is to assure that the product is of high quality and also to make sure that there is proper distribution and storage.  Also one of the conditions is that efficacy data should be available.  Any claim must be able to be substantiated by proper efficacy data.  Also safety data must be available for target animals, and also safety for the human consumer and also environmental safety; and insure prudent use, especially for antimicrobials.  In the case of antibiotics, we have to insure that they are properly used so that there is no transfer of resistance which can be able to compromise human public health.
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Good drug quality is important from the viewpoint of animal health, that is in terms of efficacy, and also animal products intended for human consumption.  There is a need for GMP, harmonization of GMP.  For example, I know currently that in the US, EU, and Japan there is a very strong attempt to harmonize.  That is the VICH, to harmonize the requirements either for GMP or most of the requirements.  So most national laws should insure good quality, good assurance during manufacture.  So basically in quality, we are trying to emphasize the fact that the drugs should be of high quality so that the human consumer or the target animal is well protected.
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Now we can have mutual recognition of manufacturing or import authorization should be encouraged.  In our case if a product is registered or licensed in another country and this is really important in our country, one of the requirements is that the product should actually be registered in the country of origin.  Especially the label claim is such that the clinical indication is available in that country.  The only exception is that if that disease is not available in the country and most people, the reviewers, they are familiar with the various conditions.  Then they can be able to exempt that.  So certificate for sale is a requirement for most drugs if they are imported from other countries.  Raw materials should be sourced from approved and reputable outlets.  The distribution of these compounds should conform with the national and international law, and we encourage veterinarians to continue to prescribe to insure proper use.  The OIE code of practice requires that all veterinary drugs are registered with respective authorities.
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Now I am trying to review the data requirements for efficacy.  One of the fundamental objectives in efficacy is that the label claim must be supported by adequate scientific data, and because of that for new molecules data should be generated by sponsors during pre-clinical and clinical efficacy studies.  For generic compounds, bioequivalence studies should be done.  In certain cases, clinical efficacy data can substitute bioequivalence studies, and all the studies should be done according to good clinical veterinary practice.  Some of the requirements for the GCPV requires that there must be a qualified or competent investigator, there must be a proposal in place, data must be properly audited and properly documented, and there must be verification of clinical trials.  The investigator must be able to show high level professionalism, including the welfare of animal’s under trials.
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Now in terms of safety assessment, some of the requirements to test the product is that GLP must be in place and the studies include the tox data, which is basically the same.  It include some acute or chronic studies, especially if it is a new molecule.  Also if it is a new molecule, long-term study data must include carcinogenic, teratogenic, mutagenic, or multi-generational developmental studies.  Also adequate pharmacological studies should be included, and normally the studies will involve any of the laboratory animals like mice, rats, guinea pigs, rabbits, et cetera.
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Now if an antibiotic is going to be used either as a MUMS product or like any other product, we are now trying to be able to be compliant with the modern requirements by international bodies whereby studies should be done to evaluate its potential on the microbial ecology of the human GIT, and this also should involve risk-based evaluation of all antimicrobials used in food animals for their potential in human health.  Most of this evaluation should be based on known bacterial pathogens like E. coli, salmonella, campylobacter, enterococcus.  So this is really a emerging issue in the last 10 years with antimicrobial agents, and we find that a lot of antibiotics are finding their way out in agriculture, and there is a lot of concern on the public health issues and the people are getting worried, about the costs.  Due to cost, increased cost of these products and also the increased cost of research in coming up with new molecules because of possible development of resistence which can come due to either misuse or overuse of the antibiotics.
(Slide.)

In terms of safety, which is really a requirement which is just basically the same.  What you do, if it is a new compound, the reviewers will establish an ADI, and that is from ADI, then MRL will then be established.  Then the MRL can also be established, and a the authorities should ensure that all compounds for food-producing animals have a withdrawal period before the slaughterhouse.  So this process is basically the same as what you do for any other product.
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Now, you realize that a lot of products for MUMS, some of them will be used let’s say in fish.  In my country, for example, we have a few fish ponds, not really fish farms, and certain environmental studies should be done to insure that the products that are going to be used have no effect on the environment.  This is becoming increasingly important, because environmental safety is really at issue.  For example, even antimicrobials, because if you use a lot of antimicrobial agents we get a lot of transfer of resistence among the various pathogens or even known pathogens, and they can be able to transfer resistance along the food chain.  I mean, whereby the transfer can take place.  So the data is required which can be able to ascertain that the product does not have any possible side effects in the environment.
(Slide.)

Now, in my concluding remarks, I am trying to equate that.  There is the classification minor use and minor species from different countries and developing countries.  There is a difference.  This can be due to either dietary difference or it can be due to geographical difference, and there needs to be a harmonization whereby we understand when we talk about what we mean by minor species and what we mean by major so that at least there can be ways in which we can share our common understanding.  There should also be surveillance for potential for antimicrobial resistence in man and livestock.  This should be underway, and there should be regular interactions through seminars.  Workshops should be encouraged, and the harmonized regulation for these compounds should be undertaken in a global perspective and within the regions.  Competent regulatory authorities should offer training opportunities and sabbaticals for experts from developing countries. Now I must say that technically in my country, or if I take my country as a case study for Africa or most developing countries, per se we have very few drugs that are specifically meant for minor species.  I would say that most drugs are used off label, and this is basically because the markets cannot be able to sustain them.  Our fish farming is not very advanced.  We depend entirely on farming for fresh water.  We have Lake Victoria, which is very, very large.  It is in Kenya.  We have the Indian Ocean, which is very expansive.  So we have only very few aquaculture, but nonetheless we are but pawns.  I mean the aquaculture, whereby we use these drugs, and there is definitely a need, especially when it comes to MRLs.  Because currently we tend to use a lot of products that are intended for either poultry if they are fish, but we have got a few special cases where we can be able to use certain products.  Hence, it is quite important that we really come up with policies either as a priority it is very, very challenging in terms of NRSP and the CVM to come up with this program, and this can be a really good way forward in trying to bring and harmonize what happens in various regions.  

Again, we don’t have any legislation as far as MUMS is concerned.  I saw that even in Europe.  As Peter was talking about that.  We don’t have any legislation which says that you have to register a particular drug or you have to have approval for a particular drug or in a particular need.  So it is our understanding that currently the regulatory authorities are trying to come up with regulations if they approve a drug, the farmers -- say ostrich farmers may require such drugs, for example.  They are most likely to use either one for poultry, and what the veterinarians will do is that there will be an extended withdrawal period which can be like a three-times fold or four-times fold just to protect the human consumer.  That is currently what we have.  But this is nonetheless a very good initiative, and I think this is something that we can learn and be able to compare notes.  

We also have, as I was saying, if you consider for example a country like ours whereby we also have the game ranching, where we have some of them are in -- you know, once in a while you may have a sick eland.  I mean, that is not a common practice for a veterinarian there.  But if the owner of the ranch may be able to, you know, get to access to the animal, he may be able to call for assistance.  In the zoo, I would also like to share this experience with Americans, how they treat a lion or a leopard.  Are you going to give a dose for the dog or are you going to give a dose for the cat?
  (Laughter.)

So I don’t know whether.  If you are going to use ampicillin for maybe for treatment, whether you are going to use a dose for a cat.  Is there a need that you should come up with a product specifically for the wild animals?  Yet we know the dog and the cat belong to the same family.  Thank you very much.
  (Applause.)

DR. CRAIGMILL:  Thank you very much.  I will just talk loudly for a second while we wire our next speaker.  Our next speaker is Dr. Tatsuro Sekiya.  He is currently a senior veterinary officer in the Office of Veterinary Drugs at the National Veterinary Assay Laboratory.  He is a veterinarian, and he has worked as a technical officer at the Ministry of Agriculture, Forestry, and Fisheries in Japan since 1993, primarily involved with drug residues in food-producing animals.  He has also been a data reviewer, and with quality testing of drugs, GMPs, GLPs, et cetera.  Dr. Sekiya, please.  Welcome.