Comptroller General OF THE UNITEDS TATES FDA’sR egulation Of Gentian Violet Appears Reasonable The FSood and Drug Administration has not approved the use of pntian violet as a food additive! or as an animal drug. GAO found no indication that FDA’s position was unreason- able or that regulatory actions taken by FDA were improper. In 9 of 10 cases where FDA regulatory actions were challenged in court, the courts agreed with FDA’s position on the use of gentian violet for veterinary purposes. GAO also reviewed allegations of f DA harass- ment of three firms that have sold or request- ed FDA approval to sell veterinary products containing gentian violet, No evidence was found to substantiate these charges. H RD-80-91 AUGUST 14,198O For sale by: Superintendent of Documents U.S. Government Printing Office Washington, D.C. 20402 Telephone (202) 783-3238 Members of Congress; heads of Federal, State, and local government agencies; members of the press; and libraries can obtain GAO documents from: U.S. General Accounting Office Document Handling and information Services Facility P.O. Box 6015 Gaithersburg, Md. 20760 Telephone (202) 2756241 COMFY-ROLLER GENERAL OF THE UNITED STATES WASHINCTQN. D.C. 20248 B-199509 ,/The Honorable Herman E. Talmadge, Chairman (JCJ" Committee on Agr,iculture, Nutrition, and Forestry ,# lJ United States Senate Aa The Honorable Jesse Helms Ranking Minority Me3 nb er Committee on Agriculture, Nutrition, and Forestry United States Senate This report discusses the Food and Drug Administra- tion's (FDA'S) regulation of gentian violet as an addi- tive to animal feeds and as an animal drug. The report addresses concerns about whether FDA acted improperly in regulating gentian violet and dis- cusses FDA's dealings with three companies that have marketed this product --Animal Health Products, Inc., Dan-Mar Enterprises, Inc., and Naremco, Inc. We found no evidence that (1) FDA officials exhibited malice against those companies, (2) FDA's regulatory machinery had been improperly used to force any of the companies off the market, or (3) FDA had been unresponsive to ef- forts made by the companies to resolve problems concern- ing the adequacy of safety and effectiveness data they submitted to FDA. As arranged with the Senate Committee on Agriculture, Nutrition, and Forestry, 3 days after the date of this report a copy will be sent to Senator John Danforth. Unless you or Senator Danforth publicly announce its con- tents earlier, we plan no further distribution of the re- port until 30 days from the date of the report. At that time, we will send copies to the Department of Health and Human Services, the three companies involved, other inter- ested parties, and others upon request. Comptroller General of the United States REPORT BY THE FDA'S REGULATION OF GENTIAN VIOLET APPEARS REASONABLE COMPTROLLER GENERAL OF TWE UNITED STATES -D IG- E-S T- ..L - Gentian violet, a dye, has been used as an animal drug to treat many diseases and as an additive in animal feed to inhibit mold. If drugs or food are to be used in food-producing animals, the Food and Drug Administration (FDA) must approve the safety of any residues in food. FDA has not approved gentian violet for these uses and its actions in regulating gentian violet have been questioned. GAO was asked to determine whether --some FDA officials exhibited malice against certain companies and in- dividuals, --FDA's regulatory machinery was impro- perly used to force some companies out of the market, and --FDA was unresponsive to efforts made in good faith by three companies to resolve problems concerning the ade- quacy of safety and effectiveness data they submitted to FDA. These three com- panies have sold or requested FDA ap- proval to sell veterinary productscon- taining gentain violet. GAO found no evidence to substantiate any of these charges. FDA has determined that, when used for veterinary purposes, gentian violet is either a food additive or a new animal drug as defined by the Food, Drug, and Cosmetic Act, as amended. As such, gentian violet may not be marketed until sponsors have obtained FDA approval. mShsrt. Upon rsmoval, tha report fmmr date should k notrd hereon. i HRD-80-91 GENTIAN VIOLET NOT APPROVED AS VETERINARY MEDICINE As of June 1980, FDA had not approved gen- tian violet for use in veterinary products. Two firms in GAO's review, believing the history of gentian violet use and other data demonstrated safety and effectiveness, had sold products containing gentian violet. FDA has also determined that gentian violet does no+ qualify for interim food additive status. Interim status would allow products containing gentian violet to be sold while tests of safety were conducted. In two separate cases the courts have upheld FDA's determination of the status of gentian violet as an unapproved food additive and/or new animal drug. Gentian violet is currently available as a nonprescription drug for human use. As a product to control fungus and intestinal parasites, it is used for short periods of time; therefore, the pattern of human ex- posure differs from that of animal drugs. FDA's Bureau of Drugs is currently evaluat- ing whether gentian violet is generally recognized as safe and effective and whether it should continue to be available as an over-the-counter drug. (See ch. 2.) SAFETY AND EFFECTIVENESS NOT DEMONSTRATED The safety and effectiveness of gentian violet in veterinary use have 'not been demonstrated. The Food, Drug, and Cosmetic Act and FDA regulations require that, be- fore a food additive petition or new animal drug application can be approved, a product must be shown to be safe by the sponsor. Animal drugs must be shown to be effective and food additives to have utility at the proposed level of use. The acting director, Division of Drugs for Avian Species, FDA Bureau of Veterinary Medicine, told GAO that the criteria for demonstrating ef- fectiveness and utility are similar. ii According to FDA, the safety of gentian violet must be demonstrated in long-term tests designed to assess whether or not gentian violet is carcinogenic (causes cancer). These tests are necessary because gentian violet is a suspected carcinogen and also because the proposed uses could result in chronic human exposure to its residues. The effectiveness or utility of gentian violet as a mold inhibitor in animal feeds also has not been demonstrated. No firm has submitted adequate data to satisfy the safety and effectiveness requirements. Al- though three firms have indicated that they disagree with E'DA's determination that long- term tests are needed, none has used the appeal procedures established by the act and FDA regulations. (See ch. 3.) FDA REGULATORYA CTIONS FDA takes certain regulatory actions to as- sure that only safe and effective food addi- tives and animal drugs are marketed. These actions include (1) inspections, (2) adverse findings/warning letters, (3) regulatory letters, (4) product seizures, and (5) in- junctions and criminal prosecution. GAO's review disclosed that the regulatory actions taken by FDA against the three firms were not unreasonable in view of FDA's decisions that gentian violet products are unapproved as food additives and new animal drugs. FDA's determinations have, in 9 of 10 cases, been upheld by the courts. (See ch. 4 and app. III.) ALLEGATIONS OF HARASSMENT One of the firms reviewed--Naremco--alleged that certain actions taken by FDA were un- reasonable, overstepped agency authority, and/or deliberately attempted to discredit or drive the firm out of business. While iii some statements made by FDA officials to Members of Congress were inaccurate, GAO could not conclude that these were deli- berate attempts to discredit or drive the firm out of business. Officials of the other two firms reviewed--AHP and Dan- Mar Enterprises --told GAO that they be- lieved their failure to gain approval for their products was a result of FDA's ' dealings with Naremco. These officials said that they thought FDA's refusal to permit them to market gentian violet pro- ducts was the result of FDA's desire to * restrict Naremco from selling such pro- ducts. (See ch. 5.) AGENCY AND INDUSTRY COMMENTS The Department of Health and Human Services said that in general it agreed with the contents and conclusions of this report. AHP through its attorney, stated that the report contained a fair and accurate representation of the information the firm provided to GAO. The other two firms in our review--Dan-Mar Enterprises and Naremco--declined to com- ment. (See ch. 6.) iv Contents Page DIGEST i CHAPTER 1 INTRODUCTION 1 What is gentian violet and how is it used? 1 Regulation of new animal drugs and food additives 2 Scope of review 3 2 STATUS OF GENTIAN VIOLET 4 FDA has not approved the use of gentian violet as a food additive or as a new animal drug 4 Gentian violet not generally recognized as safe 6 Court decisions support FDA's assessment of the status of gentian violet 7 Gentian violet is not exempt from the preclearance requirement of the act due to the grandfather clause of the 1962 amendments 10 Gentian violet does not qualify for interim food additive regulation 15 Bureau of Drugs position regarding availability of gentian violet as an over-the-counter drug 20 3 SAFETY AND EFFECTIVENESS OF GENTIAN VIOLET NOT DEMONSTRATED 24 Safety of gentian violet as an animal drug or food additive not demonstrated 24 Long-term studies of gentian violet being conducted by FDA 30 Effectiveness of gentian violet as a mold inhibitor in animal feeds not demonstrated 31 Administrative hearing procedures not used by firms 35 Conclusions 36 4 REGULATORYA CTIONS TAKEN BY FDA 37 Types of regulatory actions taken by FDA 37 Regulatory actions taken on firms by FDA 39 Conclusions 46 Page CHAPTER 5 ALLEGATIONS OF HARASSMENT 47 Consolidation of court cases and FDA refusal to negotiate a settlement 48 Information provided to Members of Congress on Naremco's activities 51 Advice provided to various Naremco customers and State agencies concern- ing the legality of Naremco products 53 Advice provided to a USDA official on whether Naremco products could be legally sold 54 Notification to other firms marketing gentian violet products of the court of appeal's ruling 55 Interference with Naremco's attempts to export a gentian violet food additive 56 Actions taken to preclude Naremco from marketing products at a poultry convention in 1975 58 Publication of a 1974 court decision in the 1978 "FDA Consumer" 58 No evidence that FDA's actions against Dan-Mar and AHP were unreasonable 59 6 AGENCY AND INDUSTRY COMMENTS 61 APPENDIX I Results of FDA inspection of firms in GAO's review 62 II FDA seizures of gentian violet products marketed by firms in GAO's review 69 III Court cases involving gentian violet prod- ucts marketed by firms in GAO's review 72 IV Letter dated June 18, 1980, from the Acting Inspector General, Department of Health and Human Services 76 V Letter dated June 18, 1980, from counsel for AHP, Inc. 78