Monday, April 30, 2012

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.

Saturday, April 28, 2012

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.

Wednesday, April 25, 2012

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.

Tuesday, April 24, 2012

Gary D. Osborn's Plea in Criminal Case

Today, a magistrate judge in the Northern District of Texas recommended that the district court accept Gary D. Osborn's guilty plea to a two-count information, charging violations of  21 U.S.C. Section 331(a)352(a) and 333(a)(1)--all criminal, class A misdemeanors--for introducing in interstate commerce a misbranded drug in that its label was false and misleading. Click here to see Report and Recommendation of magistrate judge.  As noted in previous blogs three people died because of misbranded colchicine injectable solution compounded at ApothéCure, Inc., where Osborn was a pharmacist.  Osborn was released on conditions that are typical of this type of case.  The next step is that the district court will most likely accept the magistrate judge's report and recommendation, thus accepting Osborn's guilty plea and then impose sentence.

Readers feel free to comment on whether pharmacists and companies that compound medications should be held criminally responsible in these types of cases?  Should criminal charges be brought only in cases where death or serious bodily injury results?  Does it matter if the death or serious bodily injury is that of an animal instead of a human?  Should a company be shut down if a death or serious bodily injury results?

Plea Hearing in ApothéCure and Gary D. Osborn Criminal Case

A hearing in the criminal case of ApotheCure and Gary D. Osborn is scheduled for 10:30 a.m. today.  It is expected that ApothCure and Gary D. Osborn will plead guilty to the two-count information, charging violations of  21 U.S.C. Section 331(a)352(a) and 333(a)(1)--all criminal, class A misdemeanors--for introducing in interstate commerce a misbranded drug in that its label was false and misleading. The defendants were responsible for introducing into interstate commerce two lots of misbranded colchicine injectable solution that led to the deaths of three people in the Pacific Northwest.  Updates on the hearing will be posted as soon as the information is available.

Monday, April 23, 2012

India No Longer Making Cisapride

Cisapride, while banned for use in humans, is a commonly used and valuable drug used for animals.  The country of India previously made Cisapride; however, their government has shut down production for human safety reasons.  Several organizations have petitioned the Indian government to reconsider.  Here is the letter that the Society of Veterinary Hospital Pharmacists wrote to the Indian government petitioning them to reconsider.  Click here.


Special thanks to Gigi S. Davidson for bringing this issue to the author's attention. 

FDA Video About Compounding

The United States Food and Drug Administration has prepared a video explaining compounding to consumers.  To view this video, click here.

FDA Statement on Compounding of Pergolide Products for Animal Use


FDA Statement on Compounding of Pergolide Products for Animal Use

March 16, 2012
On September 7, 2011, the U.S. Food and Drug Administration (FDA or Agency) approved a new animal drug application (NADA) for a product containing pergolide mesylate (NADA 141-331) marketed under the trade name PRASCEND Tablets for the control of the clinical signs associated with Cushing’s Disease in horses.
In the past, veterinarians prescribed human pergolide products to treat Cushing’s Disease in horses under the “extralabel” use provisions of the Federal Food, Drug, and Cosmetic Act. However, in May 2007, the human pergolide products were removed from the market due to concerns about cardiac side effects in humans. At that time FDA stated that it would work with the sponsors of approved human products and others to ensure that pergolide remained available to treat Cushing’s Syndrome in horses until a new animal drug application was approved for that use. FDA stated that this would include, among other things, exercising enforcement discretion as appropriate over the pharmacy compounding of pergolide for use in animals. However, because FDA has approved NADA 141-331, the conditions under which the Agency was exercising enforcement discretion no longer exist.


For additional information, click here.

FDA issues Second Warning regarding Compounded Drugs (Brilliant Blue G and Triamcinolone) from Franck's


Certain Compounded Drugs from Franck's: FDA Issues Second Warning to Physicians

  • Brilliant Blue G (BBG)
  • Triamcinolone

[Posted 04/20/2012]
AUDIENCE: Eye Care, Family Practice, Pharmacy
ISSUE: FDA has received additional reports of fungal endophthalmitis (eye infections) in patients who were given Brilliant Blue G (BBG) during eye surgery since the FDA Warning to Physicians was posted on March 19, 2012. The agency has also recently received reports of eye infections in patients who were given injections of drug products containing triamcinolone during eye surgery.
BACKGROUND: Clinicians in several states reported the adverse events. FDA, CDC, and local and state public health agencies are actively investigating these incidents.
These drugs were supplied by Franck’s Pharmacy in Ocala, Florida. Brilliant Blue G is not an approved drug in the United States. Franck’s has recalled all lots of BBG and one lot of Triamcinolone Acetonide P.F
RECOMMENDATION: The Centers for Disease Control and Prevention (CDC) has advised healthcare personnel to stop use of all sterile triamcinolone-containing products purchased from Franck’s until further information regarding the safety of these products is available.
FDA requests that practitioners report to FDA any cases of suspected fungal or bacterial infections, which have occurred within the last six months, associated with drugs labeled as sterile from Franck’s Pharmacy:
  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm1
  • Download form2 or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[04/20/2012 - Updated Warning3 - FDA]
[03/31/2012 - Press Release4 - Franck’s Compounding Lab]
Previous MedWatch Safety Alert
The United States Food and Drug Administration (FDA) Website has a specific page dealing dealing with Pharmacy Compounding, which can be found here.  As of April 23, 2012, this page contained the following information and links:

Pharmacy Compounding

Pharmacy Compounding News


Significant Compliance Actions



Compounding Surveys


FDA Alert 66-66; "APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The Requirements For The Labeling Exemptions In 21 CFR 201.122"


(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the
manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person,
and does not operate to bind FDA or the public).

Import Alert # 66-66
Published Date: 04/10/2012
Type: DWPE
Import Alert Name:
"APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The
Requirements For The Labeling Exemptions In 21 CFR 201.122"

Reason for Alert:
OASIS records indicate that a large volume of bulk chemicals which can be used as APIs in human
medicines that require NDAs, ANDAs, or INDs are being offered for entry into the U.S.

NDA Imported APIs labeled for further manufacturing and processing or labeled as chemical
substances are frequently destined for pharmaceutical processors that formulate finished drug
products. These drug substances, consigned to individuals or processors who formulate and
distribute human drugs, may be misbranded under Section 502(f)(1).

AIND Sponsors of investigational new drug applications frequently import from foreign
countries either the dosage form or the API for use in laboratory research or clinical trials.

Some persons importing APIs have found that they could obtain entry of these articles if they
simply supply an NDA or IND number at the point of entry. Districts should be alert to the
possibility that: 1) the NDA or IND number provided does not cover the source of the particular
API or 2) the persons importing the API have no authorization to refer to the particular NDA or
IND number. In the past, the persons importing an API have referred to legitimate numbers to
get their APIs released, but the APIs were not destined for use in the application referenced.

CDER and ORA are in the process of making the Establishment Evaluation System (EES)
available to the field. When available, field offices should utilize EES to search and verify the
status of an API, its manufacturer, whether it has been referenced in a valid NDA or whether
it is the subject of a valid IND. Districts that do not have access to EES should contact
DIOP, 301-443-6553 to verify this status.

(OASIS entry records can be compared to CDER records for NDAs, ANDAs, and IND
exemptions to verify the source and status of an API.)

EXEMPTION UNDER 21 CFR 201.122

API labeling invariably lacks adequate directions for use as required by Section 502(f)(1)
of the Act. However, such drugs may be subject to an exemption under 21 CFR subpart 201.122.
This regulation requires specific labeling on the package when adequate directions for use are
missing, such as "Caution: For manufacturing, processing, or repacking."

However, the exemption under 21 CFR 201.122 will not apply to a substance intended for a
use in the manufacture, processing, or repacking of the API which causes the finished article
to be a new drug, unless:

A. an approved NDA covers the production and delivery of the API to the application holder
by persons named in the application; or

B. if no application is approved with respect to the API, the label statement "Caution: For
manufacturing, processing, or repacking" is immediately supplemented by the words "in the
preparation of a new drug or new animal drug limited by Federal law to investigational use,"
and the delivery is made for use only in the manufacture of such new drug or new animal
drug limited to investigational use as provided in 21 CFR part 312 or part 511.1.

The API/manufacturer combinations listed in Attachment A appear to represent importations
of APIs to be used for the manufacture, processing, or repacking of drugs which the Act
and regulations require to be the subject of an approved NDA or a valid IND. However,
either the person receiving the API or the person importing the API appears not to meet the
statutory and/or regulatory requirements regarding labeling. Further, it appears that the Agency
has never inspected the declared manufacturer's GMPs for that imported API.

Guidance:
Detain without physical examination the APIs from the manufacturers identified in the
Red List to this Import Alert.

Districts may detain without physical examination APIs from the persons identified in the
Red List because it appears that the API is misbranded based on its lack of adequate
directions for use as required by section 502(f)(1) of the Act and its failure to meet the
requirements of the exemption found in 201.122. Persons importing these APIs may obtain
release of the detained articles if these persons can supply evidence establishing that the article is:

1. intended for pharmacy compounding that meets the requirements of section 503A of the
Act, including that the API:

a. is accompanied by a valid certificate of analysis,

b. is manufactured by an establishment registered under section 510 of the Act,

and

c. does not appear on a list of drugs identified in 21 CFR 216.24, that have been withdrawn or
removed from the market for reasons of safety or effectiveness.

2. intended for use in the manufacture, processing, or repacking of an over-the-counter
product or prescription product that does not require an NDA;

or

3. a new animal drug, or intended for use in the manufacture, processing, or repacking of a new
animal drug, subject to an NADA;

and, therefore, the API is not subject to this import alert.

OR

Persons importing APIs may obtain release of the detained articles by supplying evidence
establishing that the article is:

1. intended for use in the manufacture, processing, or repacking of a human drug that is itself
the subject of an approved NDA, and that the API is from the appropriate source; or

2. it is covered by IND requirements at 21 CFR 312.110(a).

For questions or issues concerning science, science policy, sample collection, analysis,
preparation, or analytical methodology, contact the Division of Field Science at (301) 796-6600.

This guidance is not intended to address new animal drugs or investigational new animal drugs addressed
by Import Alert number 68-09. If the imported APIs are intended for use in an NADA or INAD, refer
to Import Alert number 68-09.

If the APIs are intended for the compounding of finished drugs by pharmacies, persons
importing the APIs must comply with the requirements in 503A of the FDCA.

This guidance does not apply to excipients or APIs intended for use in OTC drugs or prescription drugs
that do not require a new drug application.

Product Description:
Active Pharmaceutical Ingredients (APIs)

Charge:
"The article is subject to refusal of admission pursuant to section 801(a)(3) in that it appears to be misbranded in that it lacks adequate directions for its intended use. [Misbranding, Section 502(f)(1)]."

OASIS Charge Code - DIRECTIONS

NOTE: Under 502(f)(1), an API must have labeling that lists adequate directions for its use unless the API is subject to exemptions from labeling found in 201.122.

For a list of firms and their products subject to detention without physical examination (DWPE) under this import aller (a.k.a. Red List), click here and scroll to the bottom of the page.

Sunday, April 22, 2012

Gary Osborn and Apothecure are Scheduled to Plead Guilty in Compounding case Charging Misbranded Drug Violations

On April 18, 2012, the United States, Gary D. Osborn and Apothecure filed a plea agreement and factual resume in the Northern District of Texas. Pursuant to the plea agreement, Osborn and Apothecure have agreed to plead guilty to the two-count information, charging violations of  21 U.S.C. Section 331(a)352(a) and 333(a)(1)--all criminal, class A misdemeanors.   ApothéCure and Gary D. Osborn are admitting that they introduced into interstate commerce a misbranded drug with a false and misleading label.  The defendants face up to a year of imprisonment.  Most likely, the defendants will receive probation and be ordered to pay a fine of $100,000.  The parties, while not agreement on the amount of the fine, have agreed that $100,000 would be a reasonable fine in this case.  Nevertheless, the United States' position is that the maximum fine can be imposed up to $250,000 for each count in the information.  The defendants have also agreed to pay restitution to the victims or community, which is mandatory under federal law.  The rearraignment and entry of the plea of guilty are scheduled for April 24, 2012, at 10:30 a.m.

Wednesday, April 18, 2012

Articles About Compounding

An excellent article written by Marie Rosenthal  entitled Compound Troubles appears in American Animal Hospital Association Trends Magazine, February 2012 with interviews of Gigi Davidson, BSPh, DICVP, Director of Clinical Pharmacy Services, NC State College of Veterinary Medicine and Hal Witt, CVT, Chair of Veterinary Marketing at Med Shop Total Care in Longview, Texas as to what to look for to make sure a compounding pharmacy is following the rules.  A subscription is required to view this article.  Click here.

The internet also has a number of  free articles about compounding.  Here are a few:

1.  The Truth About Compounding:  http://thetruthaboutcompounding.com/healthcare.html

2.  The American Veterinary Medical Association: http://www.avma.org/issues/drugs/compounding/veterinary_compounding_brochure.asp

3.  The Regulation of Pharmaceutical Compounding and the Determination of Need:  Balancing Access and Autonomy with Patient Safety:  http://www.leda.law.harvard.edu/leda/data/646/Riley.html

4.  The News Vin with a List of Articles about Compounding: http://news.vin.com/vinnews.aspx?articleId=19784


Tuesday, April 17, 2012

Makena: Example of Where FDA examined a Compounding Pharmacy


Another example where the United States Food and Drug Administration (FDA) has recently (November 2011) examined compounding pharmacies involves compounded versions of Makena, a newly approved drug for premature births, after the manufacturer provided samples of active pharmaceutical ingredients and finished product vials that failed FDA potency standards. The FDA had previously maintained it would not take enforcement action against pharmacies that compounded Makena “based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products” Click here for additional information.

FDA Foods and Veterinary Medicine Program Strategic Plan for 2012 – 2016 Draft Targets Illegal Compounding

A draft of the FDA Foods and Veterinary Medicine Program Strategic Plan for 2012 – 2016 indicates that a new enforcement strategy to address illegal compounding of new animal drugs may be a top priority of the FDA in the future.  Cases such as Franck's and ApothCure (although not a case involving animal drugs) suggest that illegal compounding of drugs has already become a key initiative of the FDA.  The draft reads:

The FVM Program is concerned about the number of unapproved animal drug products
that are being sold and marketed to animal owners and veterinarians. To reduce the risk of
harm from substandard and illegally marketed animal drugs, the program will identify new
regulatory frameworks and enforcement strategies to combat this growing area of
concern.
Key Initiatives
7.2.1: Develop risk‐based frameworks that assure quality and safety for products
that are currently being marketed without FDA approval
7.2.2:  Develop and implement an enforcement strategy that addresses the illegal
compounding of new animal drugs and removes unsafe, ineffective or copycat
animal drugs from the market

To read the entire FDA Foods and Veterinary Medicine Program Strategic Plan for 2012-2016 click  here.

FDA Division of Compliance: Inspecting Businesses that May be Manufacturing Under Guise of Compounding

The Division of Compliance of the United States Food and Drug Administration (FDA) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding.  The FDA web site contains the following statement regarding Veterinary Drug Compounding.

Inspections, Compliance, and Criminal Investigations

.9.2 - VETERINARY DRUG ACTIVITIES

CVM is responsible for inspections of therapeutic and production drugs, and Active Pharmaceutical Ingredients (APIs). Therapeutic drugs are used in the diagnosis, cure, mitigation, treatment or prevention of disease. Production drugs are used for economic enhancement of animal productivity. Examples include: growth promotion, feed efficiency and increased milk production.
Preapproval inspections are conducted pursuant to pending NADA or ANADA applications.
Post approval inspections of veterinary drugs are conducted to determine compliance with the Current Good Manufacturing Practices (CGMPs) for Finished Pharmaceuticals under 21 CFR Part 2113. These cGMPs apply to both human and veterinary drugs. Information on veterinary drugs approved can be found in the "Green Book" database accessed through CVM's website.
APIs are active pharmaceutical ingredients. Many of the APIs used to manufacture dosage form drugs are imported from foreign countries. The intended source for an API must be indicated in NADA/ANADA submissions for new animal drug approvals. Any change in a source for an API would require a supplement to the application.
Extra label drug use refers to the regulations in 21 CFR Part 5304 codified as a result of the Animal Medicinal Drug Use Clarification Act5 (AMDUCA) of 1994. These regulations set forth the requirements that veterinarians must meet to prescribe extra label uses of FDA approved animal and human drugs. The regulations describe what is a valid veterinary-client-patient relationship as well as what is considered illegal extra label use. 21 CFR Part 530 addresses issues regarding extra label use in non-food as well as food producing animals. 21 CFR 530.416 contains a list of drugs that cannot be used in an extra label manner in food-producing animals. During an inspection or investigation if you encounter any situations on suspected illegal extra label use of any FDA approved animal or human drugs or those prohibited for extra label use in food animals, you should contact CVM's Division of Compliance (HFV-230) (240-276-9200).
21 CFR Part 530 also addresses compounding of products from approved animal or human drugs by a pharmacist or veterinarian. The regulations clearly state compounding is not permitted from bulk drugs. This would include APIs. CVM has an existing CPG on Compounding of Drugs for Use in Animals (CPG 608.4007). A copy can be found on CVM's website. The Division of Compliance (HFV-230) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding. You should contact the Division of Compliance (HFV-230) at 240-276-9200 to report instances of compounding or to seek guidance on inspectional issues, or regulatory and enforcement policies.

More Trouble for Franck's


The FDA website contains the following notice regarding Franck's:

Brilliant Blue G Compounded by Franck's: Recall of Unapproved Drug - Ongoing Investigation of Fungal Endophthalmitis Cases


[Posted 03/19/2012]
AUDIENCE: Ophthalmology, Risk Manager
ISSUE: FDA has received reports of fungal endophthalmitis (eye infections) in patients who were given Brilliant Blue G (BBG), supplied by Franck's Pharmacy, during eye surgeries. Clinicians in several states reported the adverse events. FDA, along with CDC and local and state public health agencies, are actively investigating these adverse events.
BACKGROUND: The BBG was supplied by Franck’s Compounding Lab, Ocala, Florida. Franck’s Pharmacy issued a recall on March 9, 2012, of all lots of Brilliant Blue G and issued a recall letter (link below). Brilliant Blue G is not an approved drug in the U.S.
RECOMMENDATION: Immediately quarantine and return any remaining Brilliant Blue G product from Franck’s Compounding Lab. This includes all lots of Brilliant Blue G received from Franck’s.
FDA requests that practitioners report to MedWatch any cases of endophthalmitis, fungal or bacterial, that occurred within the last six months, associated with eye surgery in which Brilliant Blue G from any source was used.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:
  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm1
  • Download form2 or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[03/19/2012 - Warning Statement3 - FDA]
[03/09/2012 - Recall Letter4 - Franck’s Pharmacy] 

FDA Warning Letters and Notice of Violation Letters

To find warning letters and notice of violation letters to Pharmaceutical Companies issued by the United States Food and Drug Administration(FDA), click here  This page only covers letters issued by Headquarters and the Office of Prescription Drug Promotion.

To find warning letters issued by FDA District Offices, click here



Positions taken by Society of Veterinary Hospital Pharmacists and Former FDA Officials in Franck's Appeal


In the amicus brief filed by the Society of Veterinary Hospital Pharmacists (SVHP's), its position is clearly stated:

    Regarding the legality of traditional compounding with bulk chemicals, SVHP has adopted a "Position Statement on Compounding," a complete copy of which is available on SVHP's website. See http:svhp.org/position-statement/.   That statement recognizes that in many circumstances traditional compounding with bulk chemicals is essential to providing high quality pharmaceutical care for sick animal patients.  SVHP supports the ability of veterinary pharmacists, in consultation with veterinarians caring for animal patients in need, to compound medicines from bulk ingredients as follows:   If an FDA approved product is unavailable or not appropriate for treatment, compounding with bulk chemicals (APIs) may become necessary and required for proper treatment. The APIs/bulk ingredients used to compound an appropriate product should be of highest possible chemical grade, and the finished product should be compounded from those bulk ingredients using a formula – preferably a USP formula – with evidence-based documentation of potency and stability.  


     The legal position taken by the United States in this matter, through the Federal Drug Administration (“FDA”), is that any compounding from bulk materials by pharmacists for animals is illegal under the Federal Food Drug and Cosmetic Act (“FDCA”), 21 U.S.C. § 301, et seq., and has been since the statute was first enacted in 1938. SVHP respectfully disagrees, and believes that legal position to be incorrect.


In the amicus brief filed by Former FDA officials, they make a very persuasive argument distinguishing between traditional compounding and manufacturing of drugs.  Their summary of argument provides:



     The Federal Food, Drug, and Cosmetic Act (“FD&C Act”) did not criminalize traditional pharmacy compounding, including compounding animal drugs from bulk ingredients. Instead, the FD&C Act was enacted to regulate drug Case: 11-15350 manufacturing, which is categorically distinct from traditional pharmacy compounding. Additionally, none of the amendments to the FD&C Act reflect Congress’ intent to criminalize traditional pharmacy compounding, including compounding animal drugs from bulk substances. 

    In asserting that any compounding of animal drugs from bulk substances is unlawful per se, FDA’s policy guidance fails to adequately distinguish between traditional pharmacy compounding of animal drugs and manufacturing of animal drugs. The key difference between traditional pharmacy compounding of animal drugs on the one hand, and manufacturing of animal drugs on the other, is that the former is conducted in response to a prescription order based on a valid Veterinarian-Client-Patient relationship in the course of professional practice, whereas the latter is not so circumscribed. 

    As FDA acknowledges, its policy guidance on animal drug compounding lacks the force of law. Moreover, in issuing that policy guidance, FDA failed to comply with its own regulations, which require that, prior to issuing such guidance, the Agency must provide notice and an opportunity for interested parties to submit comments. 

    As we understand the factual record in this case, the animal drug compounding that Defendants-Appellees conduct is within the scope of traditional pharmacy practice. The district court’s decision therefore should be affirmed. 

The Former FDA Officials are careful to point out that the "factual record" on appeal did not support manufacturing of drugs.  The FDA failed to present this argument in the district court.  Frank's in his brief argues that this argument is waived on appeal.  Normally, if an issue is not raised in the district court it can be considered waived by the appellate court.  If the 11th Circuit wants to avoid the hard issue of what is traditional compounding and what crosses over into manufacturing then it can do so by applying the waiver doctrine.



Monday, April 16, 2012

Additional Amicus Curiae Briefs filed in the Franck's case

Additional Amicus Curiae Briefs have been filed in the Franck's case.  Both briefs support the affirmance of the district court decision:

1.  Society of Veterinary Hospital Pharmacists

2.  Former FDA Officials

See Previous Blog Entry

ApothéCure and Gary D. Osborn Criminal Case: Hearing Set

A Rearraignment/Guilty Plea hearing has been set in the ApothéCure and Gary D. Osborn criminal case for April 24, 2012, at 10:30 in the Northern District of Texas.  See Notice filed by district court.  Most likely with the filing of a criminal information, instead of the grand jury issuing an indictment,  and this notice of rearraignment, a plea agreement has been reached between the parties and at the rearraignment the defendants will enter a plea of guilty.


Prior State Proceedings:


  In November 2010, the Texas state board reprimanded Osborn's pharmacist license of Osborn because he had failed to ensure that an error did not occur during the making of that compounded sterile preparation of colchicine.  The Texas state board fined ApothéCure $125,000 and its license was placed 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.

Declarations Filed in Franck's district court proceeding

In the appeal to the 11th Circuit in the Franck's case, the court, pursuant to the federal appellate rules, is normally only allowed to consider what was part of the record in the district court. In other words, the appellate court cannot consider evidence or information that was not presented in the district court.  In the district court, the parties filed a number of declarations or sworn statements by various individuals, including the following:

Declaration of Loyd V. Allen, Jr.