CPG Section 608.400 Compounding of Drugs for Use in Animals

Compliance Policy Guide Section 608.400 is critical to understanding the FDA's policy regarding compounding of drugs for use in animals.  This section discusses when the FDA will defer to the states and when the FDA will possibly exercise enforcement action.  It also list the factors the FDA will consider in determination whether to exercise enforcement action.  A link to Section 608.400 is provided under useful links. A copy is also provided here.  

CPG Sec. 608.400 Compounding of Drugs for Use in Animals

Sec. 608.400 - Compounding of Drugs for Use in Animals (CPG 7125.40)

This compliance policy guidance is intended to provide guidance and instructions to FDA staff, industry, and the public for obtaining information to help fulfill the Agency's plans regarding the compounding of drugs for use in animals. The compliance policy guidance does not create or confer any rights for or on any person and does not operate to bind the Food and Drug Administration (FDA) or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations. It is intended for FDA personnel, industry, and the public and is available electronically to the public.

INTRODUCTION

This document provides guidance to drug compounders, veterinarians, and the staff of the Food and Drug Administration (FDA) on how the Agency intends to address compounding of drugs intended for use in animals. This guidance describes FDA's current thinking on what types of compounding might be subject to enforcement action.

BACKGROUND

FDA announced the availability of Compliance Policy Guide (CPG) section 608.400 entitled "Compounding of Drugs for Use in Animals" on July 3, 1996 (61 FR 34849), to provide guidance to FDA's field and headquarters staff with regard to the compounding of animal drugs by veterinarians and pharmacists for use in animals. There is a potential for causing harm to public health and to animals when drug products are compounded, distributed, and used in the absence of adequate and well-controlled safety and effectiveness data or adherence to the principles of contemporary pharmaceutical chemistry and current good manufacturing practices. Use of compounded drugs in animals can result in adverse reactions and animal deaths. Furthermore, because the pharmacokinetics and depletion times for residues from compounded products intended for use in food-producing animals are not known, the assignment of an extemporaneous withdrawal time may result in potentially harmful residues in food. Inactive ingredients, such as excipients and vehicles, from unapproved or unknown origins may also pose additional risk (e.g., Freunds adjuvant, a carcinogen).
FDA is updating this guidance to be consistent, to the extent practicable, with the scope of compounding permitted under regulations implementing the Animal Medicinal Drug Use Clarification Act of 1994, to describe what factors FDA will consider in exercising its enforcement discretion regarding compounding of drugs intended for use in animals, and to ensure the consistency of its policies with regard to compounding of drugs intended for use in humans and in animals.

DISCUSSION

The Federal Food, Drug, and Cosmetic Act (the Act) does not distinguish compounding from manufacturing or other processing of drugs for use in animals. FDA acknowledges the use of compounding within certain areas of veterinary practice. The current state of veterinary medicine requires products to treat many conditions in a number of different species, some of which are known to have unique physiological characteristics. Furthermore, FDA regulations specifically permit the compounding of products from approved animal or human drugs under the conditions set forth in 21 CFR 530.13. This activity is not the subject of this guidance.
However, FDA is greatly concerned about veterinarians and pharmacies that are engaged in manufacturing and distributing unapproved new animal drugs in a manner that is clearly outside the bounds of traditional pharmacy practice and that violates the Act (e.g., compounding that is intended to circumvent the drug approval process and provide for the mass marketing of products that have been produced with little or no quality control or manufacturing standards to ensure the purity, potency, and stability of the product). These activities are the focus of this guidance. Pharmacies and veterinarians who engage in activities analogous to manufacturing and distributing drugs for use in animals may be held to the same provisions of the Act as manufacturers.
With regard to compounding from bulk drug substances, two Federal Appeals Court decisions, United States v. Algon Chemical Inc., 879 F.2d 1154 (3d Cir. 1989) and United States v. 9/1 Kg. Containers, 854 F.2d 173 (7th Cir. 1988), affirmed the FDA position that the Act does not permit veterinarians to compound unapproved finished drug products from bulk drug substances, unless the finished drug is not a new animal drug. The principle established by the court applies equally to compounding by pharmacists.
Neither the Act nor its implementing regulations exempt veterinarians or pharmacists from the approval requirements in the new animal drug provisions of the Act, 21 U.S.C. Section 360b. In the absence of an approved new animal drug application, the compounding of a new animal drug from any unapproved drug or from bulk drug substances results in an adulterated new animal drug in violation of section 21 U.S.C. Section 351(a)(5). The compounding of a new animal drug from an approved human or animal drug also results in an adulterated new animal drug in violation of 21 U.S.C. Section 351(a)(5), unless the conditions set forth in 21 CFR 530.13(b) are met.

DEFINITIONS

1. Bulk drug substance, as defined in 21 CFR 207.3(a)(4), means any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug, but the term does not include intermediates used in the synthesis of such substances.
2. Compounding does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling
3. A valid veterinarian-client-patient relationship (valid VCPR), as defined in 21 CFR 530.3(i), is one in which:
   1. A veterinarian has assumed the responsibility for making medical judgments regarding the health of (an) animal(s) and the need for medical treatment, and the client (the owner of the animal or animals or other caretaker) has agreed to follow the instructions of the veterinarian;
   2. There is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s); and
   3. The practicing veterinarian is readily available for follow-up in case of adverse reactions or failure of the regimen of therapy. Such a relationship can exist only when the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of examination of the animal(s), and/or by medically appropriate and timely visits to the premises where the animal(s) are kept.

POLICY:

Generally, FDA will defer to state authorities regarding the day-to-day regulation of compounding by veterinarians and pharmacists of animal and human drugs that are intended for use in animals. FDA anticipates that, in such cases, cooperative efforts between the states and the Agency will result in coordinated investigations, referrals, and follow-up actions by the states.
However, when the scope and nature of activities of veterinarians and pharmacists raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new animal drug, adulteration, or misbranding provisions of the Act, FDA has determined that it will seriously consider enforcement action. In determining whether to initiate such an action, the Agency will consider whether the veterinarian or pharmacist engages in any of the following acts:

1. Compounding of drugs for use in situations (a) where the health of the animal is not threatened; and (b) where suffering or death of the animal is not likely to result from failure to treat.
2. Compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving prescriptions issued within the confines of a valid VCPR.
3. Compounding of drugs that are prohibited for extralabel use in food-producing or nonfood-producing animals, under 21 CFR 530.41(a) and (b) respectively, because the drugs present a risk to the public health.
4. Compounding finished drugs from human or animal drugs that are not the subject of an approved application, or from bulk drug substances, other than those specifically addressed for regulatory discretion by the FDA, Center for Veterinary Medicine, e.g., antidotes (see Appendix A). Inquiries about compounding from unapproved drugs or bulk drug substances should be directed to CVM, Division of Compliance, 301-827-1168.
5. Compounding from approved human drugs for which FDA has implemented a restricted distribution system.
6. Using commercial scale manufacturing equipment for compounding drug products.
7. Compounding drugs for third parties who resell to individual patients, or offering compounded drug products at wholesale to other state licensed persons or commercial entities for resale.
8. Failing to operate in conformance with applicable state law regulating the practice of pharmacy.
9. Compounding of drugs for use in animals where an approved new animal drug or approved new human drug used as labeled or in conformity with 21 CFR Part 530 will, in the available dosage form and concentration, appropriately treat the condition diagnosed.
10. Compounding from a human drug for use in food-producing animals if an approved animal drug can be used for the compounding.
11. Instances where illegal residues occur in meat, milk, eggs, honey, aquaculture, or other food-producing animal products, and such residues were caused by the use of a compounded drug.
12. Labeling a compounded drug with a withdrawal time established by the pharmacist instead of the prescribing veterinarian.
13. Labeling of compounded drugs without sufficient information, such as withdrawal times for drugs for food-producing animals or other categories of information that are described in 21 CFR 530.12.

The foregoing list of factors is not intended to be all inclusive. Other factors may be appropriate for consideration in a particular case.

REGULATORY ACTION GUIDANCE:

District offices are encouraged to consult with state regulatory authorities to assure coherent application of this guidance to establishments that are operating outside of the traditional practice of pharmacy.
Follow FDA's laws and procedures prior to sharing non-public information with the public, or federal, state, local, and foreign government officials.
FDA-initiated regulatory action may include issuing a warning letter, seizure, injunction, and/or prosecution. Charges may include, but need not be limited to, violations of 21 U.S.C. Sections 351(a)(2)(B), 351(a)(5), 352(a), 352(f)(1), and 352(o) of the Act. Tissue residue violations are covered under 21 U.S.C. Section 342(a)(2)(C)(ii) of the Act.
Issued: 6/26/1996 (7/3/1996 Federal Register)
Revised: 7/8/2003 (7/14/2003 FR)

APPENDIX A

LIST OF BULK DRUG SUBSTANCES FOR COMPOUNDING AND SUBSEQUENT USE IN ANIMALS TO WHICH CVM WOULD NOT ORDINARILY OBJECT

• Ammonium molybdate
• Ammonium tetrathiomolybdate
• Ferric ferrocyanide
• Methylene blue
• Picrotoxin
• Pilocarpine
• Sodium nitrite
• Sodium thiosulfate
• Tannic acid 

The Compounding and Pharmacy Practices Branch of the United States Food and Drug Administration (FDA)

At the FDA, the Office of Unapproved Drugs and Labeling Compliance, Division of Prescription Drugs, Compounding and Pharmacy Practices Branch is responsible for compliance and enforcement issues relating to compounding.  More specifically, according to the FDA website, the Compounding and Pharmacy Practices Branch responsibilities include: 

• Working cooperatively with states to oversee compounded drug products and protect consumers from harmful compounded drugs
• Directing field inspections and investigations and recommending, directing and/or coordinating case development and compliance actions relating to compounded drug products and other related pharmacy practices.
• Providing enforcement and litigation support and guidance for compounded drug products and other related pharmacy practices
• Reviewing and developing legislative proposals and implementing regulations, policy and guidance documents, enforcement strategies, and outreach activities related to pharmacy compounding and other pharmacy-related issues.
• Using risk based assessments to identify and prioritize compounded drugs for regulatory action and developing compliance strategies to address violations.

Francks case: Appellate Process Explained

Jurisdiction of 11th Circuit Court of Appeals

The Franck's case is currently pending at the 11th Circuit Court of Appeals.  I thought a short discussion of federal appellate procedure might be helpful.  The 11th Circuit Court of Appeals is a federal court with appellate jurisdiction over the district courts in the following districts:

1.  Middle District of Alabama
2.  Northern District of Alabama
3.  Southern District of Alabama
4.  Middle District of Florida
5.  Northern District of Florida
6.  Southern District of Florida
7.  Middle District of Georgia
8.  Northern District of Georgia
9.  Southern District of Georgia

What the 11th Circuit Can Consider

A federal appellate court is generally only allowed to consider the record that was established in the district court.  There are some exceptions, but for the most part if the evidence or information was not presented in the district court then the 11th Circuit will not be allowed to consider it on appeal.  The same principle generally applies to legal arguments made on appeal.  If the argument was not made in the district court, there is a strong chance it will be considered waived or forfeited on appeal.  Again there are exceptions.

Oral Argument

Once briefing is done in Francks, the case will be submitted to a panel of three judges to review the district court decision. Approximately three-fourths of the court's cases are decided on the briefs submitted by the parties, while the remaining cases include oral argument. Oral arguments are held in the Elbert P. Tuttle United States Court of Appeals Building in Atlanta, Georgia and are open to the public. Oral arguments are also held in Florida (Jacksonville and Miami) and Alabama (Montgomery). Most likely in Franck's the judges will set the case for oral argument because the parties have requested oral argument.  Each side's attorneys will get 15 minutes to argue the position of the party represented.  The amicus curiae who filed briefs in the Franck's case may participate in oral argument only with the court's permission.

Timing of Decision

After oral argument, the appellate court will issue a decision.  There is no time limit on when the decision has to be issued.  Some cases can take over a year before an appellate court issues its opinion.

The Written Opinion

The opinion will consist of a written analysis that reviews the district court's decision.  The appellate court can (1) affirm the district court decision; (2) reverse the district court decision; (3) modify the district court decision or (4) remand the case for further the district court to make further factual findings.  This decision will be binding only in the states listed above that make up the 11th Circuit Court of Appeals.  It will be persuasive authority in all other states, but those federal courts will not be bound by the decision and can reach a totally contrary result if presented with the issue.  Only if the issue is decided by the United States Supreme Court will the decision be binding in all federal courts.

Options of Losing Party

At that point, the losing party can file a (1) petition for rehearing before the three judge panel, (2) file a petition for rehearing en banc before the full 11th Circuit Court of Appeals (3) petition for certiorari
to the United States Supreme Court or (4) accept the decision and implement whatever it says.  A court of appeals is not required to grant a petition for rehearing before the three judge panel or before the full court.  Furthermore, the United States Supreme Court would not be required to grant certiorari.  Each of the first three options has different legal standards that must be met.      

What is the Next Scheduled Event in Francks


The FDA has requested an extension of time to file a reply brief to Frank's response brief.  The FDA's reply brief is currently due on May 1, 2012.  A copy of the FDA's reply brief will be posted as soon as it is filed.

DOJ Press Release: Dallas Compounding Pharmacy Owner Pleads Guilty in Connection with

Department of Justice
Office of Public Affairs
FOR IMMEDIATE RELEASE
Tuesday, April 24, 2012

Dallas Compounding Pharmacy Owner Pleads Guilty in Connection with
Misbranded Drug Shipment, Shipment Led to Three Deaths in Pacific Northwest

Gary D. Osborn and his corporation, ApothéCure Inc., pleaded guilty today in the U.S. District Court for the Northern District of Texas to two misdemeanor criminal violations of the Food, Drug and Cosmetic Act (FDCA). The pleas are in connection with ApothéCure’s interstate shipment of two lots of misbranded colchicine injectable solution that led to the deaths of three people in the Pacific Northwest.

ApothéCure, which is located in Dallas, is a compounding pharmacy. Compounding Pharmacies create particular pharmaceutical products to fit the unique needs of patients by combining appropriate ingredients.

Colchicine is used to prevent gout attacks (sudden, severe pain in one or more joints caused by abnormally high levels of a substance called uric acid in the blood) in adults, and to relieve the pain of gout attacks when they occur.

The government’s charges were based on ApothéCure’s February 2007 shipment of 72 vials of compounded colchicine to a now-defunct medical center in Portland, Ore. On March 19, 2007, a patient in Yakima, Wash., who received colchicine from this shipment, died after receiving the infusion. The medical examiner determined that the cause of death was multiple organ failure and acute colchicine toxicity.

On March 30, 2007, colchicine from ApothéCure was administered to two other patients who were suffering from back pain. Within hours of receiving the colchicine injections, both patients became seriously ill, were taken to local hospitals, and died shortly thereafter. The medical examiner in Oregon determined colchicine toxicity to be the cause of death for both patients.

FDA testing of vials selected from the lethal shipment revealed that some of the vials were super-potent, containing 640 percent of the level of colchicine declared on the label. Other vials were determined to be sub-potent, and contained less than 62 percent of the declared levels on the labels.

“This plea shows that the Department of Justice will enforce the Food, Drug and Cosmetic Act against responsible corporate officers of companies that fail to control the quality of their products,” said Stuart F. Delery, Acting Assistant Attorney General of the Civil Division of the Department of Justice. “The drugs mixed by Mr. Osborn’s company were not merely misbranded, but lethal. Drug makers of all sizes, from large corporations to small compounding pharmacies, have a duty to ensure their products are safe.”

Sentencing is scheduled for July 27, 2012.

This case was investigated by Food and Drug Administration’s Office of Criminal Investigations, which referred this matter to the Justice Department. The case is being prosecuted by Trial Attorneys John Claud and Patrick Runkle of the Civil Division’s Consumer Protection Branch.

Previous State Court Proceedings and Other Pending Civil Court Proceedings against Gary D. Osborn and ApotheCure

Before the federal government brought criminal charges against Gary D. Osborn and ApothéCure, there were state proceedings in Oregon and Texas.  The Pharmacy Board of the State of Oregon filed a Notice of Proposed Civil Penalty. The board reviewed the case and voted unanimously in 2007 to issue a civil penalty not to exceed $1,000 per violation. Click here to see press release.

Oregon's Attorney General filed a complaint in Marion County Circuit Court.   ApothéCure, Inc., was not registered with the Oregon Board of Pharmacy as required by law. Oregon's lawsuit alleged that the unlicensed company unlawfully sold dangerous prescription drugs in Oregon including Colchicine, a highly toxic drug that must be used with great care to avoid injury and death.  In this Oregon case, Osborn and ApothéCure entered into a Stipulated General Judgment, which provided that ApothéCure was out-of-business in Oregon until all necessary licenses were obtained and a $500,000 penalty was paid.   

In November 2010, the Texas State Board of Pharmacy reprimanded Osborn's pharmacist license because he had failed to ensure that an error did not occur during the making of the compounded preparation of colchicine.  The board fined ApothéCure $125,000 and placed its license on probation for one year with the condition that the pharmacy develop and implement a continuous quality improvement program for preventing and handling dispensing errors.  The Texas States Attorney General also filed a lawsuit against ApothéCure and Osborn. Click here to see petition and here for press release.

The families of two of the colchicine victims filed wrongful death lawsuits and reached confidential settlements with ApothéCure.  The third family is negotiating a settlement with the company
On February 19, 2008, Hartford Lloyds Insurance  Company filed a civil action against Osborn and ApothéCure in the Northern District of Texas in case number 3:08-cv-00288-P.  This case is still pending. 

Cheryl A. Thompson has written an article posted on the The American Society of Health-System Pharmacits' website entitled Criminal Charges Not Necessarily Criminalization of Medication Error. Click here to read this article.