Single-patient trials, extemporaneously compounded products and pharmaceutical care
Extemporaneously compounded pharmaceutical dosage forms and other alternatives to commercially available drug products have become increasingly important components of therapy in recent years. Studies of extemporaneously compounded dosage forms have identified the following advantages: significant cost savings,1 improvements in therapeutic response,2 and capabilities in meeting the needs of special population groups.3 However, as is often the case, controversy has developed concerning their role in patient care and modern pharmacy practice. As one author was calling for research on extemporaneous formulations to meet the needs of pediatric populations,4 another was wondering if extemporaneous compounding (at least in the field of dermatology) might be at "the end of the road,"5 citing "...the unpredictable nature of compounded medications, both in effectiveness, as well as safety and stability of such products."
In the late 1970s, a few large-volume compounding operations, together with therapeutic claims for some notorious compounded products, drew the attention of the US Food and Drug Administration. Its major concern was whether certain compounding activities by pharmacists could be construed as manufacturing, an activity under its jurisdiction. The Sene-X case, in which federal prosecutors obtained an injunction preventing the continued dispensing of GH-8 by Seven Freedom Pharmacy in Ft. Lauderdale, Florida, was a seminal federal legal action that enunciated a basis for subjecting the compounding of pharmaceutical dosage forms to new drug provisions of the Food, Drug, and Cosmetic Act.6 Thereafter, scholars began to debate the ethical and legal implications of extemporaneous compounding for the first time, and whether-and to what extent-practitioners should promote these services to other health professionals and the public.7 Subsequently, some studied the need for enhanced information that would enable compounding pharmacists to produce the most effective product possible8 and argued that ethical challenges to extemporaneous compounding can be largely resolved if the product is of sufficient quality to provide the therapy needed for the patient.9
The role of extemporaneously compounded dosage forms arises out of the definition of pharmaceutical care and an understanding of the pharmaceutical-care process, in which the pharmacist explicitly lists and ranks alternative approaches to resolve patients' drug therapy-related problems. Because it is recognized that commercially available dosage forms sometimes fail to meet the needs of individual patients, the role of extemporaneously compounded dosage forms is accepted when marketed dosage forms are not available or must be ruled out because they are inappropriate or ineffective for achieving the desired therapeutic outcome.
Documentation of the achievement of desired outcomes is a key element of pharmaceutical care, and an important tool in assessing the achievement of outcome is the use of single-patient, or N-of-1, trials, controlled trials of drug therapies in individual patients. Based on sound methodological and statistical procedures, these trials can greatly assist the clinician in monitoring the outcomes of a course of therapy and in deciding whether the treatment is having the desired therapeutic effect for an individual patient. Documenting the effectiveness of extemporaneously compounded products, and carefully conducting single-patient trials is a valuable professional service by a pharmacist that can be used to assess outcomes of many therapies, including marketed drugs-both for approved indications and novel uses.
This article explores the philosophical and practical basis for including the preparation of extemporaneously compounded dosage forms as a component of pharmaceutical care. It also discusses how single-patient trials are conducted; and, for those pharmacists who wish to conduct single-patient trials, the references provide a list of useful resources.
Pharmaceutical Care and the Pharmaceutical-Care Process
In a frequently cited discussion in the recent pharmaceutical literature, Hepler and Strand define pharmaceutical care as "...the responsible provision of drug therapy by a pharmacist for the purpose of achieving specific outcomes that improve a patient's quality of life."10 National professional associations, the pharmacy education community and regulatory and accreditation agencies subsequently have recognized the delivery of pharmaceutical care as the central commitment of the modern profession of pharmacy. Therefore, the justification for the use of alternative therapies and extemporaneously compounded dosage forms rests on the role these therapies play in delivering pharmaceutical care.
Subsequent to the development of the philosophical model for pharmaceutical care, Hepler, Strand and many others have written extensively-and conducted applied research-on processes that characterize pharmaceutical care in practice. Strand and her coworkers in Minnesota have described the elements of the pharmaceutical-care process, which are summarized as follows:11,12
1. Establish the pharmacist-patient relationship.
2. Collect, synthesize and interpret relevant data.
3. List and rank the patient's drug-related problems.
4. Establish a desired therapeutic outcome for each problem.
5. Determine feasible pharmacotherapeutic alternatives.
6. With the patient, choose the best drug, dose, regimen, formulation, etc.
7. Design a therapeutic drug-monitoring plan.
8. Implement the individualized regimen and monitoring plan.
9. Follow-up to measure success.
The determination that an extemporaneously compounded dosage form is appropriate for an individual patient begins with the third stage of the process, when the pharmacist identifies that a drug therapy-related problem exists. In most cases, the patient will be experiencing symptoms that are not relieved by a marketed product or experiencing unacceptable side effects from a marketed product that is otherwise effective or facing a lack of availability of a marketed product. In making this determination, it is critical that the pharmacist know the desired outcome of therapy and that he or she has made an assessment that the outcome is not being achieved.
With the desired outcome in mind, the pharmacist can identify feasible therapeutic alternatives that can be expected to achieve the outcome. In developing a list of alternatives, the pharmacist should consider the following types of solutions to patient drug therapy-related problems:
* No action (or discontinuation of current therapy);
* Psychotherapy or counseling;
* Nutritional approaches;
* Exercise and/or physical therapy;
* Medical devices;
* Marketed drugs, both legend and over the counter;
* Extemporaneously compounded dosage forms; and
* Alternative medicine.
The Alternative Therapies Compromise
The next question concerns the role or relative importance of alternative therapies in rendering drug-related care to patients. The proposed/generally accepted hierarchy is as follows: drugs are considered after nondrug approaches, and marketed drugs are considered before extemporaneously compounded dosage forms or alternative medicines. This explicitly recognizes that drug therapy is inherently risky and that marketed drugs have more clearly established benefits and risks for patients than do extemporaneously compounded products or other alternative therapies. In spite of the anecdotal evidence of the effectiveness of extemporaneously compounded drug products, the following realities remain. First, standards for production, assay or stability may not be available.8 Second, variability in the marketplace of bulk drug sources as well as finished products is common.13 Finally, because extemporaneously compounded products have not been subject to large-scale, controlled clinical trials, the risk-benefit profile for these agents is not established. Therefore, the use of compounded products or alternative medicines instead of marketed products is considered to involve a compromise.
When it is determined that an extemporaneously compounded product is likely to be the best alternative for a given patient, it is important for ethical and practical reasons that the patient understand the nature of the alternative therapy compromise and that the decision to use an extemporaneously compounded product be reached within the context of an established pharmacist-patient-physician relationship.