Warning Letters Matter

Warning Letters Matter

Posted by Kim Egan  on June 27, 2012

Attached is our monthly summary of selected FDA Warning Letters recently made public by FDA. Of particular note:

FDA cited one manufacturer of drug components and its immediate shipper for violation of Import for Export provisions because of failure to provide IFE records and a report, despite multiple requests by FDA.

FDA issued a warning letter to one company for promoting unapproved new drugs that made unsubstantiated claims about treatment of a wide variety of conditions, including cancer, autism, schizophrenia, multiple sclerosis, hepatitis C, and HIV infection.

FDA cited another company for making unsubstantiated therapeutic claims, including treatment of cancer and Alzheimer’s disease, about its mushroom supplements that FDA considered unapproved new drugs. In addition to inclusion of these claims on the company’s website, they were also supplemented by metatags used to bring consumers to the site.

FDA issued a warning letter to the manufacturer of a laser system for the unapproved new use of a device, as well as violation of Electronic Product Radiation Control requirements because of failure to submit product reports and file its annual report.

FDA also cited a tobacco company for violating the agency’s regulations restricting the sale and distribution of tobacco products to minors by promoting its “No Nonsense Rewards” program, wherein customers were offered a check in exchange for providing proof of purchase of specially marked packages of the company’s moist snuff product.

FDA continues to focus on Good Manufacturing Practices and posted warning letters for the following devices: steam sterilizers, an anti-embolism wrap system, lower limb prosthetics, bone densitometers, anesthetic delivery systems and respiratory therapy equipment, contact lenses, external penile rigidity devices, infusion pumps and urological catheters, neurosurgery and hemostatic devices, wound and burn dressings, temperature indicators, dental prosthetics, plasma coagulation control devices, an enteral infusion pumps, sterile syringes, an orthogonal percussion adjusting instrument, a turning medical bed, a pharmaceutical compounding device, telemetry devices, electrocardiogram monitoring equipment and software devices, a non-sterile blood pressure monitor, a total knee replacement system, a ventricular assist system, and a powered muscle stimulator device. In addition to the cGMP violations, FDA cited twelve companies for MDR violations, two for unapproved devices, two for unapproved new uses of a device, one for Report of Corrections and Removal violations, and two for Registration and Listing violations.

FDA also posted seven warning letter for cGMP violations regarding finished pharmaceuticals and dietary supplements. In addition to the cGMP violations, FDA cited one company for labeling violations, and one company for unapproved new drugs and field alert report violations.

The statistics are:

- 24 letters re cGMP device violations;

- 9 letters re medical device reporting (Animas Corporation (including cGMP violations), Health Science Products, Incorporated (including cGMP violations), APC Medical Limited (including cGMP and registration and listing violations), Teh Lin Prosthetic & Orthopedic, Inc. (including cGMP violations), Sorin Group Deutschland GmbH (including cGMP violations), The Lasik Vision Institute, Newman Lasik Centers LLC, Soring Medical Technology (including cGMP violations) and Okamoto Industries Inc. (including cGMP violations));

- 7 letters re cGMP pharma violations;

- 6 letters re unapproved new drugs (Herbal Extracts Plus, LLC, Agora Publishing Inc., Natural Health Team, The hCG Drops LLC, Mushroom Wisdom, Inc., and BioAnue Laboratories, Inc.);

- 3 letters re unapproved new use of devices (Medical Quant USA (including cGMP violations), Merit Medical Ireland Ltd. and BioElectronics Corporation);

- 2 letters re unapproved new devices (Akers Biosciences, Inc., and Spencer Forrest, Inc.);

- 2 letters re tobacco product marketing and sales (The Pinkerton Tobacco Company and Tobacco Source Three LLC);

- 1 letter re an unapproved new OTC homeopathic (Schwabe North America, Inc.);

- 1 letter re an unapproved new dietary supplement (Almased USA, Inc.);

- 1 letter re unapproved new use of an OTC device (CuraeLase, Inc. (including cGMP and MDR violations));

- 1 letter re drug study violations (Betty Tuller, Ph.D.); and

- 1 letter re import for export (MedPharm, LLC).

Here is our monthly summary of selected FDA Warning Letters recently made public by FDA. The statistics for this report:

- 24 letters re cGMP device violations;

- 9 letters re medical device reporting (Animas Corporation (including cGMP violations), Health Science Products, Incorporated (including cGMP violations), APC Medical Limited (including cGMP and registration and listing violations), Teh Lin Prosthetic & Orthopedic, Inc. (including cGMP violations), Sorin Group Deutschland GmbH (including cGMP violations), The Lasik Vision Institute, Newman Lasik Centers LLC, Soring Medical Technology (including cGMP violations) and Okamoto Industries Inc. (including cGMP violations));

- 7 letters re cGMP pharma violations;

- 6 letters re unapproved new drugs (Herbal Extracts Plus, LLC, Agora Publishing Inc., Natural Health Team, The hCG Drops LLC, Mushroom Wisdom, Inc., and BioAnue Laboratories, Inc.);

- 3 letters re unapproved new use of devices (Medical Quant USA (including cGMP violations), Merit Medical Ireland Ltd. and BioElectronics Corporation);

- 2 letters re unapproved new devices (Akers Biosciences, Inc., and Spencer Forrest, Inc.);

- 2 letters re tobacco product marketing and sales (The Pinkerton Tobacco Company and Tobacco Source Three LLC);

- 1 letter re an unapproved new OTC homeopathic (Schwabe North America, Inc.);

- 1 letter re an unapproved new dietary supplement (Almased USA, Inc.);

- 1 letter re unapproved new use of an OTC device (CuraeLase, Inc. (including cGMP and MDR violations));

- 1 letter re drug study violations (Betty Tuller, Ph.D.); and

- 1 letter re import for export (MedPharm, LLC).

And of particular note:

• FDA cited one manufacturer of drug components and its immediate shipper for violation of Import for Export provisions because of failure to provide IFE records and a report, despite multiple requests by FDA.
• FDA issued a warning letter to one company for promoting unapproved new drugs that made unsubstantiated claims about treatment of a wide variety of conditions, including cancer, autism, schizophrenia, multiple sclerosis, hepatitis C, and HIV infection.
• FDA cited another company for making unsubstantiated therapeutic claims, including treatment of cancer and Alzheimer’s disease, about its mushroom supplements that FDA considered unapproved new drugs. In addition to inclusion of these claims on the company’s website, they were also supplemented by metatags used to bring consumers to the site.
• FDA issued a warning letter to the manufacturer of a laser system for the unapproved new use of a device, as well as violation of Electronic Product Radiation Control requirements because of failure to submit product reports and file its annual report.
• FDA also cited a tobacco company for violating the agency’s regulations restricting the sale and distribution of tobacco products to minors by promoting its “No Nonsense Rewards” program, wherein customers were offered a check in exchange for providing proof of purchase of specially marked packages of the company’s moist snuff product.
• FDA continues to focus on Good Manufacturing Practices and posted warning letters for the following devices: steam sterilizers, an anti-embolism wrap system, lower limb prosthetics, bone densitometers, anesthetic delivery systems and respiratory therapy equipment, contact lenses, external penile rigidity devices, infusion pumps and urological catheters, neurosurgery and hemostatic devices, wound and burn dressings, temperature indicators, dental prosthetics, plasma coagulation control devices, an enteral infusion pumps, sterile syringes, an orthogonal percussion adjusting instrument, a turning medical bed, a pharmaceutical compounding device, telemetry devices, electrocardiogram monitoring equipment and software devices, a non-sterile blood pressure monitor, a total knee replacement system, a ventricular assist system, and a powered muscle stimulator device. In addition to the cGMP violations, FDA cited twelve companies for MDR violations, two for unapproved devices, two for unapproved new uses of a device, one for Report of Corrections and Removal violations, and two for Registration and Listing violations.
• FDA also posted seven warning letter for cGMP violations regarding finished pharmaceuticals and dietary supplements. In addition to the cGMP violations, FDA cited one company for labeling violations, and one company for unapproved new drugs and field alert report violations

FTC Workshop To Look at Pet Med Pricing

FTC Workshop To Look at Pet Med Pricing

Import Alert 66-66

Import Alert 66-66

(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: 04/26/2012

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).

FY 2013 Food and Drug Administration Congressional Justification

The Food and Drug Administration conducts annual and multi-year budgeting in support of the nationwide public health protection programs administered by FDA.

The FDA produces three major budget submissions a year (HHS in June, OMB in September, and Congress in February). The budget documentation for Fiscal Year 2013, can be found here.

Jeffrey N. Gibbs Statement on Behalf of Dr. Gooberman's before NJ Board of Pharmacy Regarding Compounding Naltrexone Pellets

Statement
Of
Jeffrey N. Gibbs, Esq.
Hyman, Phelps & McNamara, P.C.
Washington, D.C.
Regulatory Counsel to Lance Gooberman, M.D.
Before The
New Jersey State Board of Medical Examiners
Special Committee Investigatory Hearing

January 17, 2000
This statement is provided on behalf of Dr. Lance Gooberman, M.D. It describes the legal and regulatory status of the practice of pharmacy compounding. It is offered to demonstrate that the practice of pharmacy compounding is legal under both federal law and New Jersey state law, that the regulatory requirements for ensuring the safety and effectiveness of compounded drugs differ significantly from the requirements for manufactured drug products, and that Dr. Gooberman's practice of compounding naltrexone pellets for subcutaneous implantation in patients undergoing opiate detoxification is consistent with those requirements.
Introduction
Compounding is an integral part of the practice of pharmacy. It is legal in all fifty states. Tens of thousands of compounded dosage forms are dispensed each day in the United States.¹
In New Jersey, compounding is defined as "the act of preparing pharmaceutical components into medications, pursuant to an authorized prescriber's medication order, including, but not limited to prescription compounding, and intravenous admixture preparation."² Like other states, New Jersey state law imposes specific requirements on the practice of compounding. For example, specific New Jersey Statutes require compounded prescriptions to be filled in the amount and with the drugs as prescribed by the practitioners.³ limit who may compound drugs and under what conditions,⁴ and establish training,⁵ documentation,⁶ and handling and delivery requirements for compounded prescriptions.⁷
However, nothing in New Jersey law says that a pharmacist must have a specified amount of data before compounding a drug, or that a physician must have a specified amount of data before prescribing a Compound drug. And, in fact, requiring a specified amount of data in advance is entirely incompatible with compounding. Physicians often prescribe a compounded drug to meet the unique needs of a single patient. Obviously, there can be no prior clinical experience in that situation.
The practice of pharmacy compounding is distinctly different from the process of drug manufacturing. The U.S. Pharmacopoeia (USP), an authoritative reference for establishing drug standards, describes the characteristics that differentiate compounding from manufacturing. They include: "the existence of specific practitioner-pharmacist-patient relationships; the quantity of medication prepared in anticipation of receiving a prescription or a prescription order; and the conditions of sale, which are limited to specific prescription orders."⁸
The USP has established a monograph that describes the standards for pharmacy compounding. USP took this action in express recognition of the importance of compounding. Significantly, although USP sets our detailed standards for compounding, it does not require that there be test done before a drug is compounded.
Similarly; the National Association of Boards of Pharmacy (NABP), to which most state boards of pharmacies belong, has created detailed standards for drug compounding, NABP's standards have been widely adopted by the states. However, the NABP's standards do not require that a pharmacist or physician possess any clinical data before compounding.
Compounding is most frequently necessary when the patient requires a drug that is not available commercially. Because approval of a new drug application is a time consuming and expensive process, manufacturers generally only develop drugs in the strengths and dosage forms that are most likely to ensure a return on their investment. If a particular patient needs a drug in a different strength or dosage form, compounding is the means by which the physician can provide the drug to that patient. Compounding is also useful for medications that are not stable and which must be prepared in small quantities, or when the patient is allergic to something (e.g. a dye) in the commercially available form of the drug.
In 1938, Congress passed the first statute regulating the distribution of drugs. As subsequently amended, federal law requires that before the drug may be marketed, the drug company must demonstrate that he drug is safe and effective for its intended use. As a result, drug companies must undertake one or more clinical studies of sufficient size to demonstrate the safety and effectiveness of the product.⁹ By contrast, a compounded drug is not intended for general use. Thus, the regulatory scheme for ensuring the safety and effectiveness of compounded drugs is necessarily different than that for manufactured drug products.
In 1997, Congress established the regulatory scheme that now governs the practice of pharmacy compounding. The strategies selected by Congress to ensure the safety and effectiveness of compounded drugs clearly reflect the characteristic differences between compounded and manufactured drug products. The federal regulatory scheme focuses on controlling the process of compounding. It does not require a statistically significant assessment of the safety and effectiveness of the final drug product, as that assessment would be irrelevant to the needs of the patient for whom the compounded prescription was prescribed.
Pharmacy Compounding: The Federal Regulatory Requirements
Prior to 1997, the Food and Drug Administration (FDA) had taken the position that pharmacies that compounded were subject to the new drug approval (NDA) and good manufacturing practice (GMP) requirements of the Federal Food, Drug, and Cosmetic Act (FDC Act). According to the FDA, every time a pharmacy compounded a drug, it needed to comply with the GMP and NDA provisions of the FDC Act. While FDA said that in the exercise of its enforcement discretion, it would normally not require pharmacies to comply with the GMP and NDA requirements, the agency also said that it had the power to compel compliance. Under those standards, compounded drugs were - n theory - subject to the same standards for safety and efficacy as drugs manufactured for use in the general population. Congress disagreed with that approach.
In 1997, Congress amended the FDC Act by adding Section 503A which governs the practice of pharmacy compounding. Section 503A which governs the practice of pharmacy compounding. Section 503A exempts compounded drugs from the new drug approval and good manufacturing practice requirements of the FDC Act, provided that the drugs are compounded in accordance with specified criteria.
These criteria include limiting compounding to licensed pharmacists and physicians, and restricting the type and quality of the materials that may be used. It is through adherence to these criteria that the safety and efficacy of compounded drug products is achieved. Therefore, a pharmacist who compounds a drug in accordance with these criteria is exempt from the NDA, GMP and labeling provisions that govern the development of drug products manufactured for use in a broader population of patients.¹⁰ Thus, there are no requirements for evaluating the safety or efficacy of the final compounded drug in animal or human trials. The statute does not require test data even if a compounded drug is widely prescribed and dispensed to thousands of patients.
In enacting the pharmacy legislation, Congress was well aware of the fact that new drugs generally require controlled clinical trials. Nevertheless, Congress exempted compounded drugs from the need to meet this standard. Congress recognized that compounding, by its very nature, should not have to meet the safety and efficacy standards that apply to manufactured drugs.
Compounding of Depo-Naltrexone Pellets
Dr. Gooberman's practice of compounding depo-naltrexone in pellet form for subcutaneous implantation in patients undergoing opiate detoxification is consistent with the criteria established by Congress for pharmacy compounding in Section 503A. Section 503A provides that compounding may only be performed by a licensed pharmacist or licensed physician subject to receipt of a valid prescription for an identified Patient. Dr. Gooberman complies with this requirement because he, as a licensed physician, prescribes compounded depo-naltrexone in pellet form form for subcutaneous implantation in individually identified patients.
Section 503A also places limits on the type of drugs that may be used in compounding. According to Section 503A(b), a licensed pharmacist may compound a drug product using bulk drug substances that comply with the applicable USP or National Formulary (NF) monograph, when a monograph exists, as well as the USP chapter on pharmacy compounding. Naltrexone is covered by a USP monograph.
Any drug withdrawn from the market because it was found to be unsafe or not effective, or any drug which presents "demonstrable difficulties" for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product, may not be used in compounding.¹¹ Naltrexone is an FDA approved drug that has not been withdrawn from the market for reasons concerning its safety or effectiveness, nor has it been identified by FDA as a drug which presents "demonstrable difficulties" for compounding. Therefore, it meets these criteria.
Section 503A also places limits on the quantity of drug that may be compounded. This includes a prohibition on "regular" compounding, or compounding in "inordinate" amounts, of drug products which are essentially copies of commercially available drugs.¹²
Naltrexone is not commercially available in the pellet form prescribed by Dr. Gooberman. Orally administered forms of the drug are commercially available and are currently used as adjunctive therapy during the detoxification process for the purpose of blocking the pharmacological effects of exogenously administered opioids. The utility of orally administered naltrexone is limited, however, as dosing is dependent upon patient compliance. Because the drug is prescribed for patients whose lifestyles may make compliance extraordinarily difficult, the rate of relapse is high. Depo-naltrexone in the pellet form is considered significantly different from oral naltrexone. Thus, compounding of the drug in this form is not considered compounding of a drug that is otherwise commercially available, and this limitation therefore does not apply to the pellets compounded by Dr. Gooberman.
While compounding may be limited to a single formulation for a single patient, that is not necessarily the case. Under Section 503A, a pharmacist can compound larger quantities of a drug, such as depo-naltrexone, for multiple patients and still not need FDA approval. Accordingly, Dr. Gooberman's prescription of depo-naltrexone for multiple patients is not inconsistent with Section 503A.
The law also intends there to be limits on the quantity of compounded drugs that may be shipped across state lines by individual pharmacists or pharmacies. Specifically, Section 503A seeks to limit the interstate distribution of "inordinate amount" in this context is to be established by FDA with each state through a Memorandum of Understanding (MOU). FDA has said that it will not enforce this provision until an MOU is adopted. FDA has not yet adopted an MOU.
Thus, Dr. Gooberman's prescriptions for compounded depo-naltrexone comply with FDA's requirements. He therefore does not need to have clinical data to prescribe this compounded medication.
___________________________
1. International Academy of Compounding Pharmacists, The Art and Skill of Compounding,http://iacprx.org/about_compounding.htm.
2. N.J.A.C. § 13:39-1.2(1999).
3. N.J.A.C. § 45:14-16(1999).
4. N.J.A.C. § 13:39-9.8(1999).
5. N.J.A.C. § 13:39-11.7(1999).
6. N.J.A.C. § 13:39-11.10(1999).
7. N.J.A.C. § 13:39-11.13(1999).
8. United States Pharmacopeia, Pharmacy Compounding Practices, USP 24-NF 19,2118.
9. 21 U.S.C. § 355(d)
10. 21 U.S.C. § 353a.
11. 21 U.S.C. § 503A(b)(1)(D).
12. 21 U.S.C.§ 503A(b)(1)(D)