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.

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.

Declaration of Shelton T. Bradshaw

Declaration of  Gigi S. Davidson

Declaration of William T. Flynn

Declaration of Paul W. Franck

    Supplemental Declaration of Paul W. Franck

Declaration of Rick Pelphrey

Declaration of Kenneth Pettengill

Declaration of James B. Powers

Declaration of Dr. Robert C. Saunders

Declaration of Emma Singleton

Declaration of Kevin Stoothoff

Because these declarations were all apart of the record in the district court, they are part of the record on appeal and can be considered by the appellate court.

Criminal Charges in a Compounding Case: Exercise of Federal Authority

The Criminal Information filed against ApothéCure, a major compounder in the United States, and Gary D. Osborn charges violations of 21 U.S.C. Section 331(a), 352(a) and 333(a)(1)--all criminal, class A misdemeanors.  Basically, the information charges that  ApothéCure and Gary D. Osborn introduced in interstate commerce a misbranded drug in that its label was false and misleading.  Criminal misdemeanors under the federal system are criminal offenses eligible for terms of imprisonment that do not exceed one year but are more than six months in length by federal statute. See 18 U.S.C. 3559(a)(6)  Under the federal system, the district court also uses the advisory United States Sentencing Guidelines to determine the range and actual punishment.  Both the criminal charges in ApothéCure and the attempt to obtain an injunction in Franck's show the FDA and DOJ attempting to exercise its federal jurisdiction to regulate and punish compounders who step out of bounds.  It will be interesting to see how far the federal courts allow the FDA and DOJ  to exercise this power against other compounders who violate the law.   The appeal  in Franck's while only binding on those states in the 11th Circuit Court of Appeals--Alabama, Florida, and Georgia--will be precedent setting with the possibility, no matter the outcome, of making its way to the United States Supreme Court.  The other possibility if DOJ/FDA loses the appeal is for there to be a legislative fix attempting to define the parameters of federal jurisdiction to regulate this area of the law.