March 5, 2007
Larry D. Sasich, Pharm.D., M.P.H., FASHP
LECOM School of Pharmacy
Consultant, Public Citizen’s Health Research Group
Traditional pharmacy compounding involves the manipulation of Food and Drug Administration (FDA) approved dosage forms such as tablets or capsules into, for example, solutions or suspensions for an individual patient having difficulty in swallowing. The FDA exercised its discretion and did not regulate traditionally compounded drugs as unapproved new drugs even though they are because of the small scale of the activity and that in rare cases the practice is medically useful.
In the late 1980s, FDA field inspectors found that some pharmacists were in possession of small scale manufacturing equipment and were producing large quantities of untested and unapproved prescription drugs. The FDA’s attempts to curtail this small scale manufacturing led to an acrimonious confrontation between the agency and compounding pharmacists that continues to this day.
In the mid-1990s compounding pharmacists made at least two attempts to pass legislation to protect the growing compounding industry from FDA scrutiny. Both attempts failed. Provisions in the 1997 Food and Drug Administration Modernization Act (FDAMA), a must pass bill reauthorizing prescription drug user fees needed to operate the FDA, carved a safe harbor for pharmacy compounding. Ultimately, these provisions of FDAMA were stricken after a Supreme Court decision on First Amendment grounds over advertising restrictions in the compounding provisions.
Recently, there have been media reports of injury and death tied to pharmacy compounded drugs and there have been millions of doses of potentially dangerous pharmacy compounded copies of regulated drugs released into the marketplace. The reports of harm generally occur only when there are a sufficient number of patients, usually a relatively small number, harmed in a unique way that raises the suspicion of the media. These reports come from widely divergent parts of the U.S. as the compounding pharmacy industry is comprised of widely scattered small scale producers, namely, community pharmacies, throughout the country operating independently.
The size of the pharmacy compounding industry is unknown and there is no requirement for compounding pharmacists to report problems with their products to any regulatory authority. A compounding industry trade group suggests that there may be between 800 and 900 pharmacies involved in non-traditional compounding with sales that exceed $2.0 billion per year. Because of no reporting requirement, media reports of harm from pharmacy compounded products represent only the tip of an iceberg.
Pharmacy compounding is a basic patient safety issue. The public has an expectation, if not right, that the pharmaceutical market place is free from potentially dangerous untested products promoted for unsubstantiated uses. Legislation should clearly define legitimate traditional pharmacy compounding while protecting the public from prescription drugs produced by an industry that can operate largely outside of the ability or resources of state and federal regulatory authorities to conduct meaningful oversight.
The draft Safe Drug Compounding Act of 2007 shares a number of common elements with the pharmacy compounding provisions of FDAMA, but appears to avoid the First Amendment problems of FDAMA. In general, this proposed legislation, as written, would curtail many, but not all, of the activities of compounding pharmacists that potentially jeopardize the safety of the public.
General Comments on the Safe Drug Compounding Act of 2007
Page 3 line 10
The definition of a sterile drug product should include that there is an absolute absence of viable microbes in the final finished product.
Recommend that “aqueous based” be removed and read “(C) that is a solution for inhalation; or …”
This would prevent the possibility of a compounding pharmacist preparing a non sterile non aqueous based product for inhalation.
Page 5 starting at line 1
This section should specifically state that the authority to compound can not be delegated to a non-pharmacist or a non-physician. Anecdotally, compounding is largely done by non- or minimally trained technicians.
Page 6 starting at line 8
Defining a bright line between compounding and manufacturing based on a specified number of dosage units proved to be problematic under the pharmacy compounding provisions of FDAMA. This will be addressed in greater detail below.
Page 8 starting at line 19
This provision of the draft bill allows for the development of a drug approval process distinct from the process that is currently used by the FDA to approve new drugs. A similar provision existed in the pharmacy compounding provision of FDAMA. This section will be discussed in greater detail below in the responses to the questions asked by the HELP Committee staff.
Page 9 starting at line 5
The source of bulk drug substances used by compounding pharmacists is a significant concern. Traditional pharmacy compounding rarely if ever requires the purchase of a bulk drug substance to fill a single prescription for an individual patient. The public safety would be better served if there were a prohibition against the use bulk drug substances for human compounding. This would be in line with the present laws and regulations for veterinary compounding.
Page 10 starting at line 8
There is no legitimate medical need for compounding injectable drugs from with non-sterile bulk drug substances. This activity should be prohibited.
Page 11 starting at line 3
These comments apply, in general, to all disclosure statements intended for consumers that are included in the draft language of the bill.
The disclosure statement as written is much too long and assumes that the consumer is familiar with the risks of pharmacy compounding and has some understanding of the FDA’s drug approval process. Also, the average consumer may not be aware of the serious injuries that have occurred from pharmacy compounded drugs and that the Federal and State governments have not been able to prevent these injuries with their current manpower and resources.
The following factual disclosure statement is suggested:
This drug has not been tested for safety and effectiveness and is not approved by the FDA for any purpose. This drug was not produced under conditions meeting FDA Good Manufacturing Practice guidelines to ensure content, potency, purity, and stability.
The disclosure statements should also be clearer for prescribers so that they understand the potential liability that they face in prescribing a pharmacy compounded drug. The disclosure language as it now reads in the draft bill appears to relieve compounding pharmacists of liability for the products they produce which should not be permitted and places the liability solely on the shoulders of prescribers.
Page 12 starting at line 4
In addition to providing relevant information from labeling that it is required by the FDA, the draft bill should also specify that this information be provided by the compounding pharmacist to the consumer in writing.
In addition, the FDA must require that a generic Medication Guide be required to be distributed to consumers with each new and refill prescriptions for all pharmacy compounded drugs informing consumers of the risks of pharmacy compounded drugs and that pharmacy compounded drugs are not approved for any use by the FDA. The FDA currently has the regulatory authority to require Medication Guides for drugs that are deemed to present significant public health concerns and clearly pharmacy compounded drugs fall in this category.
Responses to Specific Questions Asked by Senate Health. Education, Labor, & Pension (HELP) Staff
Page 6, line 8, should the bill more precisely define the term “limited quantities”, or provide for or require a process by which FDA could define it? More generally, should FDA be able, or required to define a volume of compounding that would be considered to be manufacturing?
Response to Question 1:
During the attempt to implement regulations after the passage of FDAMA in 1997 the issue of defining manufacturing numerically was problematic. If, for example, manufacturing were defined as 100 dosage units or more, then a pharmacist preparing 99 dosage units would be compounding. If the same pharmacist prepared 101 dosage units of the same drug this pharmacist would be manufacturing. There is no difference in the quality or safety of drug prepared by the pharmacist if 99 or 101 dosage units are produced the only difference is the quantity.
If the legislation and regulations define compounding as the manipulation of FDA approved dosage forms and certain dosage forms are prohibited from being compounded because they are demonstrably difficult to compound safely, then traditional compounding and the public are protected. This would eliminate one of the problems of trying to differentiate legitimate compounding from drug manufacturing.
Page 7, lines 6-9, is the phrase “is not immediately available for dispensing to the patient, either because the drug is not stocked or is in short supply” too imprecise? For example, could a pharmacist simply choose not to stock a drug, to necessitate compounding it? Does the intervention of the prescribing physician provide sufficient safeguards? What if the prescribing doctor is doing the compounding?
Response to Question 2:
This language is too imprecise and does offer an opportunity for abuse by compounding pharmacists to create a supplier induced demand. Because of the potential for abuse this section of the draft bill should be removed and compounding should not be permitted because of stocking or short supply.
Page 8, lines 19-24, this language repeats language in the current section 503A. Is there a workable process adequately grounded in science for FDA to use to develop this list?
Response to Question 3:
This provision of the draft bill would in effect allow consideration of drugs never approved in the U.S. to be legally sold by compounding pharmacists based on the published medical literature. This would in effect create a second drug approval process with a much lower standard than the FDA’s current standard. Recent reports suggest that the peer reviewed medical literature can be easily manipulated and that the boundary between science and promotion has been compromised in the published medical literature.
The FDA currently has the authority to audit clinical trials sites to ensure that the information the agency uses in making regulatory decisions is valid. Medical journal editors do not have this authority or the resources to conduct such audits. The FDA operates by reviewing data submitted by manufacturers to make determinations of safety of efficacy.
Access to unapproved drugs such as pharmacy compounded drugs can occur through several legal mechanisms, including enrolling in clinical trials, a special exception or compassionate exemption, an emergency Investigational New Drug (IND), and a Treatment IND. The appropriate FDA review division can expedite such a request. If an expedited request is granted the prescribing physician and compounding pharmacist must obtain local Institutional Review Board (IRB) approval.
Page 16, lines 21-25, how easy or difficult will it be for FDA to do this review?
Response to Question 4:
This section should clarify the definition of a drug as a final finished dosage form rather than as a bulk drug substance.
The draft language of the bill should read “… a dosage form that presents demonstrable difficulties for compounding …” rather than “a drug product.” During the efforts to implement FDAMA, the International Academy of Compounding Pharmacists (IACP) argued that individual drugs, as separate chemical entities or bulk drug substances, should be evaluated for demonstrable difficulty in compounding. This would be an impossible task for the FDA to undertake because of the very large number of drugs involved.
Consumer groups argued that a drug is a final finished dosage form not the chemical, or bulk drug substance. This is in line with the FDA’s drug approval process that reviews final finished dosage forms for safety and efficacy, not only the bulk drug substance. The FDA did begin to develop a list of dosage forms that were demonstrably difficult to compound for safety reasons that included sterile products, timed release dosage forms, and transdermal drug delivery systems
By prohibiting the pharmacy compounding of specific dosages that should not be attempted to be produced outside of FDA regulated facilities for safety reasons, traditional pharmacy compounding would be protected as would consumers.
Pages 17-18, should the report of adverse events be limited to “serious” adverse events, made more often than semi-annually, or required for all compounded drugs, not only those distributed across state lines?
Response to Question 5:
Reporting should include all adverse events and manufacturing problems whether or not the compounded product was distributed across sate lines. Serious adverse events should be reported to regulatory authorities within 15 days.
Page 23, lines 11-16, is there a way for FDA to work with state Boards of Pharmacy on these inspections?
Response to Question 6:
Neither the FDA nor state Boards of Pharmacy have the resources or technical expertise to inspect every pharmacy in the U.S. that may be engaged in the small scale manufacturing of prescription drugs. Anecdotally, some Boards of Pharmacy appear to have been co-opted by compounding pharmacists making cooperation between the FDA and Boards of Pharmacy unlikely.
The only viable solution under the circumstances is legislation and implementing regulations that draw a bright line between traditional pharmacy compounding and manufacturing. This will simplify the process and regulation oversight and serve as a deterrent to the compounding pharmacists who rationalize their business based on their perceived ambiguity of the present law and regulations.
Page 24, lines 4-7, what specific amounts should be authorized for appropriations to FDA to carry out the bill?
Response to Question 7:
A substantial increase in appropriations would be necessary to carry out the requirements of this bill.
Should the bill include misbranding or adulteration provision for compounded drugs that fail to comply with the bill’s requirements?
Response to Question 8:
Yes. In addition, punitive penalties should be proposed.
 These comments do not necessarily represent the official position of the LECOM School of Pharmacy unless otherwise noted.