2009: Legal issues in the pharmaceutical management of bovine reproduction Legal issues in the pharmaceutical management of bovine reproduction 1 M. G. Riddell, Jr. 2 3 American Association of Bovine Practitioners, Box 3610, Auburn, AL, USA 4 5 Abstract 6 The ability for the bovine practitioner to implement reproductive management 7 programs is scientifically well-based and clinically proven. However, as is being 8 encountered in many areas of food animal medicine, science is no longer the major 9 determinant of how a veterinarian practices or how a producer manages. Extra-label drug 10 use (ELDU) allowed under the Animal Medicinal Drug Use Clarification Act was not 11 extended to drugs used for production purposes, such as reproduction. Therefore, ELDU 12 of drugs for reproductive purposes is not technically allowed in the Code of Federal 13 Regulations (CFR). Compounding of drugs from raw pharmaceutical agents, except for a 14 few specifically listed antidotes, is a violation of the CFR. Further, the use of illegally 15 compounded products in food animals is ill-advised not only due to the legal and liability 16 issues, but also because of a potential consumer perception issue. A final point to 17 consider is the consumer reaction when current bovine reproductive management 18 programs are presented to the consuming public by anti-agriculture activists. 19 Keywords: AMDUCA, compounding, management, reproduction, extra-label 20 21 AMDUCA and ELDU in reproductive management protocols 22 The Animal Medicinal Drug Use Clarification Act1 (AMDUCA) of 1994 and the 23 implementing regulations2 were limited to drugs used for therapeutic purposes only. 24 269 Numerous comments to the proposed rule supporting the extension of the regulations to 25 drugs used for reproductive management were considered but denied in the final rule. It 26 is important to note that AMDUCA applies only to Food and Drug Administration (FDA 27 or the Agency) approved drugs. The current situation has resulted in any extra-label use 28 of reproductive drugs being illegal. The U.S. FDA has adopted an unofficial position of 29 regulatory discretion. Any official position would require the generation and publication 30 of a Compliance Policy Guideline (CPG) and the FDA has not indicated that it would 31 consider taking this action. 32 The FDA’s reasoning behind placing low regulatory priority on the issue of using 33 drugs approved for reproductive purposes in a manner other than on the label is that these 34 drugs have been proven safe and effective, and the dose, route and species are not altered. 35 For example, the drug most often used in an extra-label manner is gonadotropin releasing 36 hormone (GnRH). GnRH is a decapeptide and poses virtually no risk of residues nor any 37 target animal safety issues. For these reasons, the Agency has suggested that they 38 currently will not pursue any actions directed at extra-label use of reproductive 39 hormones. At the same time, the FDA has indicated that they would be glad to entertain 40 and possibly facilitate the approval of additional label claims for GnRH products so that 41 the need for ELDU would be minimized or eliminated. 42 One final point which should be made regarding ELDU of reproductive drugs is 43 that of client informed consent. ELDU has been the basis for at least one major lawsuit 44 against a veterinary practice. In today’s litigious society, ensuring that clients are aware 45 of the extra-label nature of any use is appropriate. Having an informed and consenting 46 270 client is ever more important when such ELDU is not in compliance with the Code of 47 Federal Regulations. 48 Compounded drugs 49 Compounding medications from unapproved drugs or raw pharmaceutical agents 50 is illegal. References to this can be found in the AMDUCA regulations1 and in an FDA 51 CPG.3 There are exceptions in which drugs can be compounded under this CPG, but 52 these are limited to certain specified antidotes only. The most common drug 53 compounded for use in reproductive management protocols is some form of estrogen. 54 Estrogens have been proven effective in initiating follicular waves both in embryo 55 transfer programs and in routine breeding management systems. 56 However, in this case science has surpassed the veterinarian’s armamentarium of 57 approved drugs and, while the use of compounded estrogens may be tempting due to 58 effectiveness, the potential for regulatory action and consumer backlash makes the use of 59 compounded estrogens ill-advised. Currently the FDA lists one estrogen 60 (diethylstilbestrol) on the list of drugs prohibited for extra-label use in food animals. An 61 estrogen (estradiol cypionate) which was registered in 1953 but never approved has been 62 withdrawn from the market by the sponsor based upon an impending request for an 63 official approval application. 64 Of all the dugs used in cattle, both label and extra-label, the single drug with the 65 greatest “headline potential” is any form of estrogen. The average consumer’s lack of 66 familiarity with animal husbandry and modern agricultural production practices, make 67 the consideration of consumer acceptance relevant to the discussion of both ELDU and 68 the use of compounded drugs in food producing animals. This significant downside to 69 271 the use of a drug compounded from unapproved products (specific antidotes are 70 exceptions) makes such drug use illogical and irresponsible. 71 Consumer/public perception 72 Animal agriculture has numerous detractors in the form of activists. The issues 73 which are used to malign the animal agriculture industries to the consuming public 74 include, but are not limited to, animal welfare and factory farms. Because less than 1% 75 of the population of the U.S. is involved in agriculture, the activist groups find the 76 consuming public easily misled about commonly accepted, well proven, welfare-friendly 77 and accepted management practices. The portrayal of modern agriculture as factory 78 farming or intensive farm animal production is negatively compared to the typical small 79 farming operation of 50 and 60 years ago. With this as background, some of the current 80 reproduction management protocols which utilize multiple injections of various products 81 coupled with timed artificial insemination would represent easy targets for malicious mis-82 representation to the uninformed public. The point of this thread is not to argue that the 83 management protocols are indefensible, rather that the discussion will have to ultimately 84 be directed at a consuming public unfamiliar with any aspect of animal agriculture. The 85 science-based discussions held with colleagues regarding choice or efficacy of protocol 86 will not apply when the production practices are discussed in a public forum. The 87 impacts that these programs have on animal productivity, operational sustainability and 88 the production of a safe, abundant and affordable food supply will be the key 89 communication points. 90 Summary 91 272 Extra-label use of drugs in reproductive management programs is not allowed 92 under AMDUCA. Therefore, ELDU of drugs for reproductive purposes is not technically 93 allowed in the CFR. Compounding of drugs from raw pharmaceutical agents, except for 94 a few specifically listed antidotes, is a violation of the CFR. In addition, the use of 95 illegally compounded products in food animals is ill-advised not only to the legal and 96 liability issues, but also because of a potential consumer perception issue. A final point 97 to consider is the consumer reaction when current bovine reproductive management 98 programs are presented to the consuming public by anti-agriculture activists. 99 References 100 1. Animal Medicinal Drug Use Clarification Act of 1994, Pub. L. No. 103-396 101 (October 22, 1994). 102 2. Extralabel drug use in animals, 21 C.F.R. Sect. 530 (1996). 103 3. Compliance Policy Guide (CPG) section 608.400 entitled “Compounding of 104 Drugs for Use in Animals” 105 (http://www.fda.gov/ora/compliance_ref/cpg/cpgvet/cpg608-400.html) 106 273 << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /All /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages false /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness false /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages false /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages false /ColorImageDownsampleType /Average /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages false /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages false /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages false /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages false /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 300 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages false /MonoImageFilter /FlateEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ENU ([Based on 'No Compression'] [Based on 'No Compression wbleeed'] [Based on '[High Quality Print]'] Use these settings to create Adobe PDF documents for quality printing on desktop printers and proofers. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.) >> /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ << /AsReaderSpreads false /CropImagesToFrames false /ErrorControl /WarnAndContinue /FlattenerIgnoreSpreadOverrides false /IncludeGuidesGrids false /IncludeNonPrinting false /IncludeSlug false /Namespace [ (Adobe) (InDesign) (4.0) ] /OmitPlacedBitmaps false /OmitPlacedEPS false /OmitPlacedPDF false /SimulateOverprint /Legacy >> << /AddBleedMarks false /AddColorBars false /AddCropMarks false /AddPageInfo false /AddRegMarks false /BleedOffset [ 0 0 0 0 ] /ConvertColors /NoConversion /DestinationProfileName () /DestinationProfileSelector /NA /Downsample16BitImages true /FlattenerPreset << /PresetSelector /MediumResolution >> /FormElements false /GenerateStructure true /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles true /MarksOffset 6 /MarksWeight 0.250000 /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /NA /PageMarksFile /RomanDefault /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /LeaveUntagged /UseDocumentBleed false >> << /AllowImageBreaks true /AllowTableBreaks true /ExpandPage false /HonorBaseURL true /HonorRolloverEffect false /IgnoreHTMLPageBreaks false /IncludeHeaderFooter false /MarginOffset [ 0 0 0 0 ] /MetadataAuthor () /MetadataKeywords () /MetadataSubject () /MetadataTitle () /MetricPageSize [ 0 0 ] /MetricUnit /inch /MobileCompatible 0 /Namespace [ (Adobe) (GoLive) (8.0) ] /OpenZoomToHTMLFontSize false /PageOrientation /Portrait /RemoveBackground false /ShrinkContent true /TreatColorsAs /MainMonitorColors /UseEmbeddedProfiles false /UseHTMLTitleAsMetadata true >> ] >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice