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.
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." 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 practitioner, limit who may compound drugs and under what conditions, and establish training, documentation, and handling and delivery requirements for compounded prescriptions.
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 compounded 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.''
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 out detailed standards for compounding, it does not require that there be test data 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 the 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. 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 - in 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 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. [KDM: Quote legislative history re importance of compounding.]
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. 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 required 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 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. 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.
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 lifes 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 amounts" of compounded drugs. The definition of what is considered an "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.
Dr. Gooberman's New Drug Application
On May 26, 1999, Dr. Gooberman met with staff from the Division of Anesthetic, Critical Care and Addiction Products at the FDA. The purpose of this meeting was to explore the toxicological and clinical requirements necessary to obtain marketing approval for the use of depo-naltrexone in pellet form for subcutaneous implantation in patients undergoing opiate detoxification. In that meeting, Dr. Cynthia McCormick, the Chief of the Division of Anesthetic, Critical Care and Addiction Products, referred to the enactment of Section 503A in 1997. She specifically advised Dr. Gooberman that current law allows him to prescribe compounded product for his own patients and that approval of an NDA is required only for commercial marketing of a drug. Thus. Dr. Gooberman's decision to pursue FDA approval was entirely voluntary. Nonetheless, Dr. Gooberman has initiated the process for clinical evaluation of the naltrexone pellets for the purpose of seeking a NDA for this indication.
FDA advised Dr. Gooberman that he should conduct some animal studies to support his marketing application. This is a standard requirement for NDAs, and does not indicate that FDA
believes animal testing was necessary before prescribing compounded naltrexone. Dr. Gooberman has retained an expert to help him prepare the protocols for these animal tests.
During the meeting, FDA also asked that Dr. Gooberman use a GMT-compliant manufacturing facility to make the naltrexone for the animal studies. Dr. Gooberman has identified two potential manufacturers. He has been in negotiations with them to reach an agreement under which they would supply the materials for these preclinical tests. It must be emphasized that Dr. Gooberman is now undertaking these steps - preclinical testing and reaching an agreement with a supplier of preclinical trial materials - solely to support the FDA approval process. They are not necessary to compound under the FDC Act or New Jersey law.
Dr. Gooberman has began pursuing an NDA based on the interest of colleagues and his own conviction that the drug represents a public health benefit. The NDA process is time-consuming and expensive. While he hopes to interest a commercial partner in bringing the product to market, the initiation of this process demonstrates an extraordinary personal and financial commitment to expand the availability of this medication on the part of Dr. Gooberman, one that goes far beyond what physicians customarily do.
Conclusion
In conclusion, pharmacy compounding is legal under both federal and New Jersey State law. Federal law provides that compounded drugs are exempt for the NDA, GMT and certain labeling requirements if they are compounded for individually identified patients in accordance with specific criteria that are designed to ensure the safety and effectiveness of compounded drugs. A drug compounded in accordance with those
restrictions is exempt from the NDA, GNP. and labeling requirements that govern drug manufacturers, and does not need to be supported by clinical data.
Dr. Gooberman's practice of prescribing compounded depo-naltrexone in pellet form for use in individual patients for opiate detoxification is consistent with the safety and efficacy criteria established by Congress for compounded medications. Therefore, he is exempt from any obligation under federal law to conduct clinical trials to further assess the safety and efficacy of the compounded drug. His voluntary efforts to seek NDA approval for the drug demonstrates his commitment to ensuring that the drug is made available to a broader population of patients, and his willingness to meet a more demanding standard.
Compounding is likely to grow in clinical importance in the near future. Dr. Lloyd Allen, a leading, professor of compounding and a member of FDA's Committee, recently wrote:
Requiring that physicians possess clinical data before compounding would mean that residents of New Jersey would be deprived of the significant medical benefits offered by pharmacy compounding.
