The future holds great promise for the Rx-to-OTC switch, if we will collectively plan and manage that process. The impact of Rx-to-OTC switches will extend far beyond the technical and regulatory issues and implications. Certainly, pharmaceutical manufacturers, the Food and Drug Administration, and the Federal Trade Commission are at the center of this issue, but no less important are the roles of physicians, pharmacists, and consumers. The social and economical, and even logistical, aspects of the switch process should be considered as antecedents to an Rx-to-OTC switch policy, rather than as consequences to be measured after such a policy has been determined. Finally, the evolution of an Rx-to-OTC switch policy in the coming months and years should avoid the path of political and administrative expediency and it should avoid the consideration of special interests in isolation from the broader social context. The development of a sound Rx-to-OTC switch policy will occur only if the direction and demand truly comes from within the ranks of the consumers.
The Food and Drug Administration presently receives and evaluates over 40,000 case reports of adverse drug effects a year. Each report is objectively reviewed and evaluated. A causal association assessment between each drug and reaction is made. The objective causal assessments are based on four basic principles: (a) temporal eligibility, (b) dechallenge and outcome, (c) rechallenge and outcome, and (d) confounding factors. This presentation introduces the algorithm used by the FDA Division of Drug Experience and provides the basic information needed to use the FDA algorithm for making causal relationship assessments.
The method used in France since 1977 for assessing adverse drug reaction (ADRs) is based on a three-stage process: assessment of three chronological criteria (challenge, dechallenge, and rechallenge); assessment of clinical and biological findings; and a combination of chronological and symptomatological assessments to obtain a 3-degree global score (1: doubtful, 2: possible, 3: probable). Bibliographical data (previously reported or unreported ADR) are assessed quite separately; thus, the method has a good sensitivity for detecting new ADRs.
The purpose of this paper is to describe some methods for analyzing and summarizing adverse event rates from clinical trials, emphasizing, in particular, serious adverse drug events and their time of occurrence, and the impact of differential subject exposure and pretreatment status on the estimation of rates.
Within an ongoing drug surveillance program in psychiatric hospitals, the applicability of an algorithm for judgment on probability of causal relationship of adverse events and drug therapy was tested. Algorithmic inter-rater agreement was compared to agreement obtained with the conventional criteria used so far within the program in 80 cases by two raters, who had participated in the drug surveillance program since its beginning in 1979. Agreement on total judgment was comparable to results from similar studies in the literature using various algorithms, but in contrast to all these studies a higher percent of agreement (80%) was obtained with the use of the conventional criteria in this study than with the use of the algorithm (69%). Possible explanations and consequences are discussed.
Summary displays of data should illustrate narrative points made about the clinical experiment. Documentation of the source of the information selected for the critical displays should be assembled based on the data reduction steps that have occurred. Understanding and systematizing the presentation of the data reduction steps will facilitate the review of complex adverse experience data bases and allow well-informed decisions about the safety information.
Reporting of adverse events occurring during clinical trials of investigational drugs is a complex and controversial issue. Even the interpretation of the term, "adverse event," cannot be agreed upon by researchers. The ultimate adverse event, death, presents even a greater challenge. This paper presents an actual case of death during a clinical trial to illustrate a methodological approach to deal with such an event.
In the clinical development of new drugs for market approval, it is frequently impossible to design trials to provide definitive information about safety--particularly about adverse events. It is possible, however, to design most trials to provide definitive information about efficacy. Efficacy trials with new drugs should therefore be monitored for safety, and the safety profile described within and across trials. Confidence intervals are recommended as the appropriate statistical methodology for doing this. Such intervals provide an interval estimate on the unknown incidences of adverse experiences among patients who could be treated with each regimen, as well as permit a conclusion that two regimens are different.
The information contained in package inserts varies from country to country in Europe, although other regulatory aspects of data presentation are quite similar. West Germany's Drug Law of 1976 requires 11 items to be included in the package insert for both patient and health professional: name/address of manufacturer; drug name; active constituents; indications; contraindications; side effects; drug interactions; dosage instructions; method and duration of application; statement that drug should not be used after expiration date; and statement that drug should be kept out of reach of children. All information must be submitted to the Health Office at the time of application or the applicant is liable for criminal prosecution. Documentation of side effects must be complete, although no special form is required. Similarly, causality assessment needs to be made even though specific algorithms are not required. Proposed amendments to the Drug Law will include additional information to physicians concerning the overdose instructions, pharmacological properties, and bioavailability of the drug. Registration procedures are the same throughout Europe and are called Summary of Products Characteristics. Assessment reports are also required for each new chemical entity in the European Community.
Although pharmaceuticals comprise up to 40% of the health care budget in developing countries, the majority of the population does not have access to many of the essential drugs needed to treat prevalent diseases. This situation demands the development of a national formulary of essential drugs for the public sector. The approach used in developing countries is to select drugs of choice for the treatment of prevalent morbidities and avoid therapeutic duplication, unacceptably dangerous drugs, or drugs of unproven efficacy. Drugs are selected based on a review of the prevalent morbidities, health care worker training, patient characteristics, and efficacy/risk information resulting from scientifically sound studies. An added component to the formulary is the inclusion of concise, unbiased prescribing information for each drug selected. A number of product selection guidelines were proven to be effective in establishing and maintaining an essential drug formulary for developing countries. These guidelines include: 1. Selection of drugs with proven efficacy and acceptable risk; 2. Selection of minimum number of drugs needed to treat the prevalent diseases; 3. Inclusion of new products only if they are found to have distinct advantages over products currently in use; 4. Inclusion of combination products only when they provide true benefit over single ingredients; 5. Selection of drugs with clear "drug of choice" indications for prevalent diseases; 6. Evaluation of the administrative and cost impact of products; and 7. Selection of drugs with established high quality.
A strategy is proposed for estimating the average cost of answering drug information requests, comparing the factors that influence cost and controlling that cost. The cost for answering a request is based on the time it takes to answer the request, the salary of the person who answers the request, the cost of the information sources used to find the answer, and, indirectly, the frequency of requests of the same type. Request types have been defined by scope of search and formal of answer required, as textbook search/verbal answer, literature search/verbal answer, and literature search/written answer request. An empirical formula was used to calculate average costs for each request type at the Oregon Poison Control and Drug Information Center. A simple computer program was then used to generate costs over a range of changes that could be considered reasonable for each factor. The effect of modifying any of the factors in this formula demonstrated that a low volume of requests brings about the most critical change. Cost changes abruptly and may become unjustifiably high. If, for example, the volume of requests requiring literature search and verbal answer is 30 per month, the average cost for a request is $29.13; at a volume of 10 per month, the cost is $35.93; and at a volume of one per month the cost is $127.65. It is suggested that hospital pharmacy departments experiencing small frequencies of certain types of request analyze the cost in this manner and, if necessary, adopt a method for controlling the cost.
FDA allowance of comparative claims as part of the approved labeling for new prescription drugs creates special problems. Claims contained in prescription drug labeling are viewed by physicians as embodying not just the normal puffery of the manufacturer, but the considered views of government agency charged with protecting public health. Thus, labeling claims for prescription drugs have an impact and significance that promotional claims for other products do not. In the Moxam case--a dispute between Upjohn and Lilly over the FDA's approval of a comparative claim for a new Lilly antibiotic--the agency recognized this fundamental reality. Faced with the prospect of having to provide a procedure to permit competitors to challenge approval of comparative claims, the FDA has moved toward a policy of not permitting such claims in labeling, while allowing them in advertising.
To ensure that drugs are available in adequate quantity and quality for the health needs of the population and properly used, Asian governments in the past decades have exercised their sovereign rights quite independently and differently. A high number of patients per prescribing physician has consequences for drug information, in regard to both prescribers and consumers needing to self-medicate. To reliably inform patients through physicians, pharmacists, or medical auxiliary personnel is of great importance in the face of an illiteracy problem. Self- medication and illiteracy place emphasis on communication by word of mouth or by pictures. Word of mouth is the most important route, because even with a steady increase in literacy, the increase in transistor radios has been even more pronounced. For specific health information, instructional posters, with emphasis on pictures, have been very effective. Billboards do not allow adequate information disclosure needed for drugs. The opportunity to expand the coverage of consumer drug information, in that labelling for consumers gives additional relevant general health information, seems appropriate.
Individual case reports about suspected adverse drug reactions are an important source of drug safety data. Their evaluation involves, among other things, the assessment of causality. Usually it is done by expert medical evaluators according to their knowledge and experience. Subjectivity plays a big role as demonstrated by comparison of assessments of the same cases by several evaluators or by the same evaluator at a later date. In recent years, methods of causality assessment based on algorithms were introduced. In these formal approaches, items of information contribute to the assessment in a predetermined and standardized way with a logic that allows operational application. Results obtained with different methods may differ because items of information considered may not be the same and/or strength of evidence attached to them vary from one method to another. The main advantages of standardized assessment are: clear identification of items of information involved, improved communication, reproducibility of results, and the checklist function. Various implications of standardized assessment are discussed and ways to improve their performance outlined.