Regulatory Issues

1. Drug Availability

The availability of the drug may lag far behind demand for the drug, and this factor can temper the motivation of the FDA to approve its use. The lack of commercial amounts of drug supply or the expense of obtaining raw materials to make the drug could also lead to use of the drug under conditions similar to expanded use.

The synthesis of a compound may entail many steps in a small laboratory and be quite time-consuming and expensive. The initial scale-up to commercial production may leave impurities and, because the process changes, stability data may not be available. Lack of supply poses a difficult problem. If the drug is for use by patients who have incurable diseases and no alternative treatment exists, the sponsoring drug company must decide whether to institute an expanded-use protocol. If a protocol is employed, a decision must be made to determine how patients will be selected, because insufficient supply exists for all patients with the disease or condition. This was an especially troublesome problem in the trial of potential medications for AIDS (4). When treatments are offered that have even the smallest potential for effectiveness, patients with devastating illnesses and their families are willing to take enormous risks with virtually untested therapies.

2. Paperwork, Monitoring, and Control Responsibility

The expanded-use protocol does have some regulatory benefits. Because multiple INDs can drain FDA resources that would otherwise be dedicated to the approval of drugs, most expanded-use studies are required to be carried out under the supervision of the sponsor's IND. This procedure removes the FDA from any direct responsibility for monitoring the appropriate conduct of the study protocol and study sites. This procedure places the responsibility for monitoring study conduct and verifying, tabulating, and reporting the data to the FDA with the study drug sponsor. FDA maintains direct responsibility for the emergency-use protocols and the single-patient-use protocols submitted by investigators.

3. Package Insert

Marketing approval may be facilitated by the increased number of patients exposed to the investigational drug under an expanded-use protocol. Labeling of new drugs is typically conservative until the drug has been marketed and used in larger numbers of patients and on a long-term basis (if required by the indication). By employing the expanded-use protocol, which would include broader patient populations and variations of the indication, the sponsor may gain more liberal labeling from the increased exposure. However, by attempting to achieve more liberal labeling, the sponsor runs the risk that a delay in marketing approval could occur if difficulties develop in the interpretation of the data from an ex-panded-use study.

Side effects and drug interactions observed during the expanded-use study are required to be included in the package insert (which will generally increase the incidence of the side effect). By admitting patients who would be excluded from the controlled clinical study, the chance also exists that side effects and drug interactions that were not observed during the tightly controlled premarketing studies will be reported. These effects and interactions will require further characterization by the drug company and may need to be included in the package insert. In a severely ill population where the course of the disease is poorly understood, it may be difficult to ascribe causality to either drug or disease. A well-designed expanded-use protocol and study controls help to minimize the speculation that accompanies causality of adverse events during clinical trials.

During an expanded-use study (5) of FK 506 in liver transplant patients presenting with dysfunction who had failed previous treatment, it was concluded that the incidence of side effects observed during the expanded-use study was higher than in controlled trials. It was reported that the difference in serious adverse events ''may be related to the poor condition of the patient''; however, the labeling for the product had to include all incidences. The study was valuable in suggesting that FK 506 be used as an initial treatment for liver transplant patients, potentially allowing future trials and final labeling to be more precise.

Conversely, an expanded-use study of ondansetron (4) in chemotherapy patients with uncontrollable nausea and vomiting who had failed to respond to standard antiemetics were shown to respond favorably to ondansetron. This study, conducted in 190 patients, confirmed the effectiveness of ondansetron as an anti-emetic, allowed for broader labeling for the approved product, and offered hope to patients with no other alternative.

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