Charles Anello

Differences in Manufacturer Reporting of Adverse Drug Reactions to the FDA in 1984

Pharmaceutical manufacturers were ranked by the number of adverse drug reaction reports that the FDA received from them in 1984. Twenty companies submitted 79% of all the manufacturer reports. These companies were assessed in terms of their total prescriptions, hospital and drug store sales, and detailing calls. All three variables were correlated with the number of ADR reports, but dollar sales were the best predictor of report volume. Reports from the top 20 manufacturers were no more likely to have serious outcomes than those from the other manufacturers, but they were more likely to have unknown outcomes. The top 20 companies submitted NCE reports at a rate almost twice that of other companies, and their NSAID reporting rate was eight times as great. They submitted 85% of the total NCE reports, while only 73% of the NCE reports sent directly to the FDA were for products manufactured by these companies.

Sources of Spontaneous Adverse Drug Reaction Reports Received by Pharmaceutical Manufacturers

During the first quarter of 1986, 20 pharmaceutical manufacturers identified the original source for 5,744 domestic spontaneous postmarketing ADR reports. Overall, 27% of these reports originated with the field staff employed by the manufacturers and 34% originated with telephone calls made by health-care providers. The remaining 39% was derived from written provider reports, consumer reports, or the literature. Considerable variation in these percentages was found among manufacturers. Although some correlation was found between the number of field staff visits and the number of reports originating from field staff for some manufacturers, the frequency of field staff visits was not predictive of the number of reports obtained by most manufacturers.

Management of ADR Reports at the FDA

The Office of Epidemiology and Biostatistics, Division of Drug and Biologic Product Experience in the Center for Drugs and Biologics, FDA, receives about 40,000 reports each year from manufacturers and voluntarily from physicians and other health professionals. How well these reports are managed has direct public health implications. This paper reviews the current and proposed regulations on reporting adverse drug reactions (ADRs) to the FDA, reports on an internal evaluation of the procedures used for processing ADR reports, and discusses organizational and procedural changes recently implemented that relate to managing ADR reports.

STATISTICAL ISSUES OF COMPARATIVE CLINICAL TRIALS

This paper is concerned with some of the statistical issues that may be important in comparative advertisements based on data derived from adequate and well-controlled clinical investigations. Special attention is given to: (1) The appropriateness of the design; (2) the choice of the statistical model; (3) the completeness of information; (4) the completeness of follow up; (5) the choice of a comparison group; (6) the consideration of statistical power; (7) the method of handling covariables; (8) the stopping procedures; and (9) the issue of multiplicity. This paper also discusses the need for a common protocol, a consideration of interaction between clinics in multiclinic studies. The paper illustrates these statistical issues with the aim of making the reader aware of their importance with regard to comparative advertisements.

A Microcomputer-Based Data Entry System for Reporting Adverse Drug Reactions in the United States:

A microcomputer-based data entry system has been developed by the Food and Drug Administration as a method of reporting adverse drug reactions that are required by pharmaceutical manufacturers to be periodically submitted to the Agency on an official form. This microcomputer system may also be useful for other interested health professional concerned with the safety of drugs and biologics. The system provides a mechanism by which the entered data can be converted to the format acceptable for use by most currently available data management and statistical packages.

Toxic Shock Syndrome and the Vaginal Contraceptive Sponge

In lat 1984 4 reported cases of toxic shock syndrome (TSS) meeting Centers for Disease Control (CDC) criteria occurred among users of the vaginal contraceptive sponge (Today). All patients manifested fever hypotension diffuse rash desquamation nausea vomiting myalgias mucous membrane hyperemia and vaginal discharge. All were hospitalized and treated with intravenous fluids and antimicrobial agents and all recovered. Vaginal cultures in every case were positive for Staphylococcus aureus. The Today Vaginal Contraceptive Sponge introduced to the over the counter market in June 1983 is made of polyurethane impregrated with the spermicide nonoxynol-9 and is intended to provide 24 hours of contraception. During clinical trails the average woman using only this contraceptive method used 10 sponges per month. At the time the sponge was licensed the US Food and Drug Administration (FDA) required that the package insert contain a warning that clinical trials had not been large enough to assess the risk of TSS and that users should seek medical care if symtoms compatible with TSS developed. Instructions for sponge use indicate that it should not be left in place for more than 30 hours. Following a meeting with FDA representatives on December 16 the manufacturer highlighted the warning on the package insert and placed a similar warning on the outer box. Women who use contraceptive sponges should read the package insert carefully and follow the manufacturers directions. Users who experience difficulty removing a sponge and/or fragmentation should consult a physician. Women who have had TSS particularly if it was associated with the use of a contraceptive sponge or tampon should also consult a physician before beginning or resuming use of either. Postpartum women who may be at an increased risk of developing TSS should seek medical advice before using the contraceptive sponge. This report of 4 TSS cases among women using the contraceptive sponge is presented to inform physicians that a potential problem may exist and to encourage the reporting of additional cases. If one assumes that the 4 cases reported thus far were all attributable to contraceptive sponges a minimum estimate of the incidence of nonmenstrual TSS associated with sponge use would be 10 cases/year/100000 women who use contraceptive sponges as their only contraceptive method.