Therapeutic Innovation & Regulatory Science

Nonclinical studies in animals and in in vitro systems are essential steps in the development of a new chemical entity, both to demonstrate actions indicative of efficacy and to examine toxicity as a guide to safety. The scientific basis of prediction and extrapolation are examined, with special references to factors that lead to uncertainty in suggesting potential hazards in man.

A survey was conducted among members of the Clinical Section of the British Pharmacological Society. The main aims were to find out how many healthy volunteer studies had been undertaken in the year from October 1, 1986, to September 30, 1987, and how many volunteers had suffered adverse effects. A total of 7,607 individual drug administrations were recorded as part of class practical studies. Minor side effects only were noted in 6% of the volunteers. A total of 8,163 healthy volunteers were given drugs for research purpose in the year, and minor side effects were noted in 6.9%. Moderately severe adverse effects (needing medical attention) were noted in 45 subjects (0.55%), and 3 volunteers (0.04%) required hospitalization because of adverse effects, although there were no lasting sequelae. Healthy volunteer studies have a potential for adverse effects, but the risk is very small and we make a number of suggestions to improve safety.

Differences in adverse experience reporting for biologic products and drugs include different regulatory bodies and a stronger emphasis with biologics on capturing data on potential allergic responses. Other considerations for collecting adverse experience data are common for biologics and drugs. Critical steps include: (1) planning prior to construction of case report forms, (2) education of nurse coordinators and investigators, and (3) monitoring to evaluate the effectiveness of instruction. Experience gained in the development of tissue plasminogen activator, a biologic product, resulted in the following specific recommendations for collection of adverse experience data: (1) instruct investigators to report syndromes rather than individual associated signs and symptoms, and (2) instruct investigators to distinguish primary adverse experiences from adverse experiences secondary to another adverse experience. In studies of critically ill patients where large volumes of adverse experiences are expected, collection of adverse experience data without forethought to strategies for data organization may obscure rather than reveal the true adverse experience profile.

Prescription-event monitoring (PEM) is a system of postmarketing surveillance for new chemical entities that has been developed by Inman. Its principal aim is to generate hypotheses about adverse drug reactions (ADRs) that have not been identified during clinical trials. The operation covers the whole of England (total population approximately 50 million). Cohorts of 10,000–20,000 patients are identified from photocopies of prescriptions that are provided by the Prescription Pricing Authority. Event data are obtained from a standard questionnaire (green form) that is sent to the prescribing doctor at an interval after the date on the original prescription. Serious events are followed up further via the general practitioner (GP), and deaths are routinely investigated using GP medical records and copies of death certificates. Since 1984, 32 drugs have been included in PEM. The data base is used to provide examples of the methods of data analysis and further follow-up of signals. The future of PEM will be discussed in the context of the general development of pharmacoepidemiology in the United Kingdom. It is concluded that this should acquire a broader perspective, and needs to address issues of recruitment, training and dissemination of information, and that a sound academic base is required.

The difficulties inherent in distinguishing drug effects from disease occurring naturally in the community during postmarketing surveillance are emphasized. Multiple sources of confounding are possible as well as likely.

The strategies used in the United Kingdom for postmarketing surveillance of medicine are discussed. A spontaneous adverse drug reaction reporting scheme provides early warning of possible drug hazard, while a number of different information sources and methodologies may be applied to confirm or refute the signals of potential hazard. The importance of rapid and effective communication of drug safety concerns to health professionals is emphasised, as is the need for improved international collaboration in the identification and investigation of the adverse effects of medicines.

This discussion gives a broad overview of CODING, as it pertains to the storage and analysis of adverse events in clinical or spontaneous databases. It also offers a brief look at the larger perspective of the uses of medical terminology, and taxonomies in general. Although similarities in purpose exist across many different coding systems in use in the pharmaceutical industry, many problems are encountered when cross-comparisons are attempted. Some of these problems are also addressed. Finally, the discussion focuses on some of the technical, financial, and organizational issues faced by persons involved with the development and upkeep of their respective coding systems. Coding is usually a very low-visibility process, but its accuracy and quality are absolutely essential if we are to evaluate medical data in meaningful aggregates.

The development of prescription drug labeling is a cumulative and evolutionary process that begins early in preclinical investigation and continues for the life of a product. The incorporation of safety data into labeling represents a key activity of labeling development. The primary focus of this presentation is on labeling development with respect to safety information through Phase III of clinical development. The regulatory requirements for commercial labeling are reviewed, and the Investigator Brochure is presented as a form of “proto-labeling.” The informational requirements of the brochure are reviewed, and for each informational area, processes by which new data are incorporated into the successive editions of the brochure are considered. Preclinical information pertinent to drug safety is discussed briefly; the treatment of clinical trials safety data is emphasized.

“Labeling,” limited in this article to the approved prescribing information or data sheet, presents certain information about a drug on which physicians make their prescribing decisions. Questions are posed as to what is desired in labeling by physicians, regulators, lawyers, and marketers. The author's views are presented concerning what labeling is not and what it should not attempt to say. Problems in “how it is said” include: (1) the excessive use of modifying adjectives and adverbs, (2) the presentation of incidence of ADEs and the degree of risk, (3) ambiguous warnings, (4) definitions of contraindication, (5) the ADE “laundry list”, (6) “symptoms and signs” versus “diagnostic terms”, (7) clinical relevance of interactions, (8) “long-term” versus “short-term” use, and (9) “overdose”. Suggestions are made toward improving the presentation of safety (risk) information in labeling.

Over the last several decades, epidemiologic studies have played an ever-increasing role in furthering insight into the causes of and risk factors for numerous diseases. During this time, lawyers, juries, and courts have been faced with difficult questions of causation in the rapidly growing fields of toxic torts and pharmaceutical products liability, two fields heavily influenced by the increasing reliance by scientist upon epidemiologic research. Unable to resort to the traditional criteria for causation in a lawsuit, the legal profession has also placed an ever-increasing reliance upon epidemiologic data in order to answer the difficult questions raised by a claim that a particular product was responsible for the plaintiff's injury. The use of epidemiology in the courtroom has generated a good deal of controversy, largely because of the apparent willingness of courts to “bend the rules” so as to allocate the loss suffered by an innocent consumer to that of the manufacturer or distributor of the product. The courts' willingness to tread in waters considered by scientists to be shark infested has resulted in decisions based upon individual judges' perceptions of policy rather than the strict tenets of the scientific method. Further restrictions on the admissibility of epidemiologic evidence to prove the cause of an individual's injury are necessary.

The Active Permanent Workshop of Imputologists (APWI) was created in 1981. Its concern is to facilitate better understanding among all those interested in developing better assessment of causality. An international secretariat was organized, a newsletter is now published, and a comparative study of different methods of assessment is planned. A questionnaire to get an insight into member needs, etc., revealed that 60 respondents (out of 87 answers received) use one or another method to assess causality.

We describe a Bayesian method for doing causality assessment of suspected adverse drug reactions (ADRs). The method uses the specific findings in a case to transform a prior into a posterior probability of drug causation. The approach balances evidence appropriately, does not artificially constrain the weight that any piece of evidence can carry, and is completely open-ended — there is no limit to the number of case details that can be assessed. We provide a very brief overview of two ways for implementing the method (a spreadsheet program and an expert system) and describe how Bayesian assessment might fit into an integrated and coherent system to predict ADR incidence based on data from postmarketing surveillance.

Severe idiosyncratic adverse drug reactions (IADRs) are an important source of morbidity and mortality. These reactions are usually detected by assessing a series of single case reports. The Bayesian Adverse Reaction Diagnostic Instrument (BARDI) can be used for the differential diagnosis of these adverse events. BARDI calculates the posterior probability in favor of a specific drug versus other drug or nondrug etiologies of an adverse event based on background (eg, epidemiologic) and case information (eg, time of onset). Studies showed that BARDI discriminates between multiple drug and nondrug etiologies. However, its widespread use has been limited by the complexity and time required for calculations. We expanded a previously developed prototype program (MacBARDI) designed for assessing neutropenia with a Macintosh SE microcomputer to also calculate the PsP in favor of drug causation for examples of neurotoxicity, hypersensitivity, and hepatotoxicity. We will describe the application of MacBARDI to two IADRs: (1) nine cases of Guillain-Barré Syndrome (GBS) associated with zimeldine, and (2) nine cases of neutropenia occurring during the administration of mexiletine (MXL). The program decreased the time required to complete computations, facilitated the incorporation of new information, and allowed us to model the impact of changes in the value of various BARDI factors. These examples illustrate that MacBARDI makes this method more readily available for postmarketing surveillance studies of severe idiosyncratic reactions to new drugs.

The weaknesses and the nonreproducibility of most causality assessment methods could be explained, at least in part, by the following reasons: (a) they pretend to be applied to all adverse drug events, and (b) they propose levels for the various criteria but do not clearly define their limits. In order to try and resolve these issues, Roussel Uclaf has organized French consensus meetings with university experts and specialists in industrial or official pharmacovigilance. A consensus has been reached on the definition of adverse reactions, on the limits of the various chronologic criteria and on the evaluation of the clinical context. Most situations have been considered, reducing the individual interpretation and ensuring an excellent reproducibility. On the basis of these results, and using the same method for organizing the meeting, a first international consensus on drug-induced liver disorders has been recently obtained in Paris.

The objective of developmental and reproductive toxicity studies performed at Merck Sharp & Dohme Research Laboratories is to evaluate a compound's effects on fertility and to assess its effects on offspring exposed in utero and during lactation. Many of the studies follow from a well-defined set of experimental designs. To avoid delays in processing time and to allow statisticians to concentrate efforts in areas other than performing standard analyses, the Data Coordination Unit within Safety Assessment submits batch jobs which generate output from standard statistical routines. The software was written by Computer Resources in consultation with Biometrics Research. Computer systems validation procedures were carried out to verify that the application programs provided the intended results and to satisfy Food and Drug Administration (FDA) guidelines for systems development documentation. The total data processing system is referred to as the Developmental and Reproductive Toxicology Statistical Software System (DARTSSS).

Innovative new forms of information technology help get the right information to the right people at the right time. Tracking databases, integrated word processing networks, and optical disk (or image) storage and retrieval are technologies that can be integrated to increase overall efficiency and productivity. This report describes the role of these tools in the Medical Information Department of Imperial Chemical Industries (ICI) Pharmaceuticals Group. Optical storage and retrieval is a particularly effective means of improving response time, eliminating the “lost reprint problem,” and substantially diminishing filing space requirements. This particular application of information technology has led to more effective utilization of professional staff time and higher quality responses in less time.

The pharmaceutical industry is rapidly changing. There are mergers, the market is in a state of flux, the Japanese are coming, and there is globalization. Successful companies will deploy technology to meet this changing environment.

Companies are using technology to decrease the cost of drug research and to shorten the time it takes to bring drugs to market. This paper will focus on strategic uses of information technology in clinical research for the 1990s. It will discuss three key strategies, ways to identify strategic opportunities, and possible applications of technology.

The purpose of the paper is to make the reader think and find ways to use information technology more effectively in their company. A methodology to accomplish this is presented.

A system of modules is described for the preparation of core dossiers (manufacturing and controls section). It consists of individual monographs of the narrowest subject scope, such that the information required for any local drug registration dossier may be selected from the whole.

This paper describes a desktop multimedia system that integrates different types of Clinical Trial information. Data entry, medical, statistical personnel can use this tool to review information. The tool was developed using object-oriented technology. The technical and functional features of the tool are described.

The Worldwide Drug Planning System was developed as part of an integrated network of regulatory information which exists in Regulatory Affairs-International (RA-I). The primary objective of this Worldwide Drug Planning System is to provide RA-I personnel with a mechanism to assist in the planning for the worldwide registration of product candidates. The system consists of four basic parts. The first is a database of country requirements to obtain clinical study authorizations and marketing authorizations. The second is a database of project status information specific to each product under development. The third and fourth pieces are simulation programs which help determine scenarios and strategies for clinical study authorizations and marketing authorizations.