Therapeutic Innovation & Regulatory Science

Preclinical studies and testing strategies with and without the use of animal testing methods have the purpose of limiting risks whenever a new active substance is to be used as a medicinal product in humans. They should be designed in such a way as to achieve as early, risk-free, unproblematic, and economic a transition as possible from preclinical to clinical trials in medicinal products development. For this purpose the legitimate interests of subjects, patients, manufacturers (sponsors), and the scientific community as well as regulatory and competent authorities must be harmonized so as to achieve a course of action that is medicinally, ethically (also with respect to animal testing), and legally justified. The development of a new medicinal product is generally marked by a number of preclinical and clinical investigations; their sequential order with regard to contents and logic, the testing duration needed on an individual basis, and chronological overlaps when carrying out these studies are all to be determined. As every new active substance is a separate entity, investigations and testing strategies must be designed individually. The principle of flowcharts described in this text facilitates the development of a testing strategy adapted to a certain medicinal product by using decision-tree methods. At the same time, the flowchart principle allows for a structuring of the necessary scientific discussion between preclinical and clinical investigators as well as between sponsor and authorizing authority.

The clinical development of therapeutic medicines is a time-consuming and resource intensive process. The published literature documents the length of clinical phases, but there are few published reports on the number of clinical studies and the number of human subjects involved in the development of therapeutic medicines. In this Tufts Center for the Study of Drug Development investigation, clinical study data for 12 new biopharmaceutical products approved in 1994 through 2000 were analyzed and compared to the results of published clinical study data for new molecular entities (NMEs) and new active substances (NASs) approved during the same time period. We found that, on average, development of the biopharmaceuticals involved significantly fewer studies per application compared with the studies of NASs (11.8 studies vs. 37 studies) and also fewer subjects per application compared with the studies of either NMEs or NASs (1014 subjects vs. 5697 subjects for NMEs approved in 1998, 4980 subjects for NMEs approved in 1999, or 4478 subjects for NASs). A possible reason for this finding is that many of the biopharmaceuticals included in the analysis were treatments for diseases that affect a potentially small number of subjects, that is, rare, serious, or life-threatening diseases.

Recent regulatory initiatives and consensus documents have altered the conventional approach to evaluating and communicating pharmacovigilance information. While these trends may initially seem to provide opportunities to combine certain aspects of the premarketing and postmarketing safety evaluation functions, they also have the potential to obscure the substantial differences between comprehensive risk assessment in investigational and postmarketing settings. Personnel involved in evaluation of safety data from clinical trials (including studies for new indications for currently marketed products) must give special consideration to those regulatory, legal, scientific, and ethical issues that are unique to the premarketing environment. In this paper, we approach this complex topic by contrasting the risk assessment of investigational products, as summarized in the investigator's brochure, with similar, well-described risk evaluation processes that are carried out for marketed products.

This paper discusses a representative sample of the main deficiencies identified by European agencies in the “Chemical, Pharmaceutical and Biological documentation” of Marketing Authorization Applications for chemical active substances. The plan followed in the paper is that of the European Part II file. Each deficiency is illustrated by examples. Specific European references are listed, as well as new texts. The paper also comments on the presentation of the pharmaceutical dossier and expert report.

Back in the beginning of the 1990s the International Conference on Harmonization (ICH) was born with the objective of achieving greater harmonization of technical requirements for medicinal products, through an active process of discussion, debate, and review of science by international experts of the highest caliber. More than 10 years later, this article will review some of the achievements and missed opportunities of ICH in the process of harmonizing requirements and, in turn, harmonizing the way we develop medicinal products to support quality, safety, and efficacy from a regulatory viewpoint. This article will also look at new initiatives recently discussed at ICH such as M5, the Common Technical Document (CTD), and M2, the guideline that deals with the standards required for electronic transfer of regulatory information to regulatory authorities and how this will effect the way we move the technical reports into regulatory submissions and the subsequent review of these by the regulatory authorities in the future.

The importance of a favorable safety profile to the overall success of a pharmaceutical product is well known. While most of the analysis of safety data is routine and exploratory in nature, we will discuss some options to examine safety data in greater detail. Some of these options represent recent advancements in the statistical and graphical procedures to present and analyze safety data.

If no reliable information about the variance of the key response is available at beginning of a clinical trial, the use of data from the first few patients entered in the trial (‘internal pilot’) may be appropriate to estimate the variance and thus to recalculate the required sample size. We investigate the influence on existing methods of variance estimation via the Expectation-Maximization (EM) algorithm without unveiling of the treatment status. In addition, we investigate the use of a formula derived by Guenther to estimate the preplanned sample size. This simple modification could improve somewhat the existing methods for the same problem. There is no effect of the EM algorithm on the type I error rate of the existing procedures, and the effect on the type II error rate is negligible as long as the number of patients in the internal pilot is not too small. Thus, to recalculate the sample size it is not necessary to unveil the treatment status in an internal pilot with a moderate number of patients.

The paired t-test and the Wilcoxon signed-rank test are often conducted to compare two continuous outcomes from paired observations. An assumption underlying these tests is that the responses from pair to pair are mutually independent. However, the assumption is violated in certain applications such as site-specific data in periodontal research. An adjustment to the paired t-test to account for the clustering effect has been well developed. But the adjustment relies on either large sample theory or the assumption that the observations being analyzed follow a normal distribution. In this paper, we propose a permutation test for matched pair clustered data which are valid in small samples. We developed and reviewed software to carry out the proposed test. The proposed test is applied to real-life data.

In early stage drug discovery screens, the efficacy of a potential drug candidate in an in vivo assay is often judged, rather informally, on the proportion of animals that respond to the drug. Only if at least a prespecified proportion of animals respond is the drug considered active enough for further testing. This is a “simple screening strategy.” Researchers are often unaware of the properties of such strategies and what effects changing the parameters of the strategy, such as the sample size, could have. It is suggested and demonstrated here that the properties of a simple screening strategy can be easily understood by considering its true and false positive rates.

In the presence of dropout, valid statistical inferences based on longitudinal data can, in general, only be obtained from modeling the measurement process and the dropout process simultaneously. Many models have been proposed in the statistical literature, most of which have been formulated within the framework of selection models or pattern-mixture models. In this paper, we will use continuous data from a longitudinal clinical trial with a 24% dropout rate to illustrate some of the models frequently used in practice. We emphasize the underlying implicit assumptions made by the different approaches, and the sensitivity of the results with respect to these assumptions. The merits and drawbacks of the procedures are extensively discussed and compared from a practical point of view.

There has been a proliferation of active-control clinical trials comparing experimental therapies with standard ones (active control). In such cases, one often wants to know how the experimental therapy would have performed if it had been compared directly to placebo. This comparison requires 1. The observed effectiveness of experimental treatment compared to the active-control, and 2. The estimated effectiveness of the active-control therapy versus placebo (often obtained from a meta-analysis). If these two estimates apply to a common subpopulation, then two additional measures can be derived: 3. The estimated effectiveness of the experimental therapy relative to placebo, and 4. The estimated fraction of effect preserved by the experimental therapy. All four of these estimates can be described by point estimates, confidence intervals, and associated p-values. Our calculations have shown that if we use the conventional methods to compute the fraction of effect preserved based on the addition of confidence intervals, we dramatically increase the sample size required for studies of the experimental treatment versus standard therapy.

As newer therapies become the standard therapies, we can expect that we will have a sequence of comparisons required to estimate the effect of the newest therapy relative to placebo, and this can be estimated using a generalization of the methodology just described. This comparison addresses the issue of “drift” (the risk that a series of active-control trials might push the general therapy in the wrong direction by accepting therapies that are worse than previously approved therapy).

The problem of combining evidence from studies with several different treatment arms is also generalization of the methodology described previously. The solution to the problem requires that we assume that all of the odds ratios between the various treatments remain constant (1). We illustrate the method with an example from data on thrombolytics.

Centralized management of outsourced clinical trials is a relatively new concept in many contract research organizations (CROs). As pharmaceutical developers increasingly partner in the drug development process with CROs to manage their sponsored clinical trials, the role of project managers in CROs has undergone rapid transformation from its inception in the early 1970s. The roles and responsibilities of project managers in CROs have evolved along a path that is closely aligned to sponsor demands—to accelerate research and development time and save costs. In parallel, CROs have incorporated project management into the operational process of executing sponsored research as an instrument to achieve desired productivity and provide efficient and quality services to sponsors. This article examines the evolution of the structures/functions of project management and project managers, the development of project management and managers' roles and responsibilities, and the anticipated future direction as shaped by internal and external forces that will impact the divisional structure and functions of project managers in CROs.

Currently, a global change in the approach to herbal medicinal products can be observed and in many countries new regulations are developed for this class of products. Implementation of such legislation is necessary to guarantee the quality, safety, and efficacy of herbal medicinal products. The Dutch policy is to facilitate this process and to effect a smooth transition. To achieve this, the Dutch government has laid down a Royal Decree on Herbal Food Products, which aims at increasing the safety of food supplements containing medicinal herbs. In addition, it financially supports the activities of the private Committee for the Assessment of Phytomedicines. This committee's explicit goal is to set up a self-regulating system for monitoring the quality, safety, and efficacy of herbal medicinal products. For this purpose, it has developed operational methodology and explored some of the specific problems in this respect. This arrangement is made in anticipation of specific European guidelines for herbal medicinal products.

Audits of megatrials present a major challenge for sponsors as the limited resources make it impossible to audit an adequate sample of sites and patients. This article describes how by using a system-oriented approach, it is still possible to execute an effective audit plan. The trial for which this audit approach was applied had 15000 patients enrolled over 850 sites. The majority of sites were located in Europe (700); sites were spread over 27 countries. General study coordination and data management were handled by a contract research organization (CRO). Monitoring was shared between the sponsor and seven CROs. The enrollment was planned to be completed in less than 12 months.

Systems that were different from normal company practice and systems that were under the responsibility of the coordinating CRO were analyzed and critical systems were identified. The selection of systems to be audited was based on a priority ranking of the various systems. Some systems were evaluated at the coordinating CRO, others through site audits.

By focusing on the underlying systems, results could be extrapolated to all sites. Corrective actions were obtained at a study management level, which ensured that they were widely shared and followed up. This system-oriented approach can also be used for smaller size trials and project audits.

Pharmaceutical companies are now looking more to increasing numbers of Eastern European countries to conduct clinical studies. Various advantages accrue from these countries, notably cheaper cost and naïve patient populations. However, there is the danger of false economy with cheaper meaning poorer quality. Published results appear contradictory, with some confirming more major Good Clinical Practices violations in Eastern Europe than in Western Europe, while others suggest the reverse. Experience when conducting audits carried out in Eastern Europe has revealed that problems do exist. Many of the problems lie with the failure of the sponsor companies to provide adequate training for both monitors and investigators. Commitment by investigators in Eastern Europe is high and a small amount of time and finance invested in training could be rapidly repaid through high-quality studies.

There is an emerging interest in the clinical use of cannabis (marijuana), but there is almost no evidence of its efficacy. The Dutch government has a policy that aims at collecting clinical data to determine whether cannabis can be used as a medicine. An Office of Medicinal Cannabis was established in March 2000. This office will act as a regulator for the horticulture of cannabis and for clinical trials, as required by the Single Convention on narcotic drugs. It will also coordinate the research that can be done with several dosage forms of varying composition and for multiple indications. Several aspects of these elements are described. The office will also see to the prevention of leakage of the cannabis crops to illicit circuits. To this end growers will be contracted under certain conditions only. The manufacturing of the finished medicinal products will be a matter of private companies in a “free” market, regulated by the requirements of the Single Convention.

Contemporary drug development requires conducting clinical trials on an international basis. Meeting the needs for supplying the drug product to these trials must be performed in the most time effective manner. Appropriately manufactured, packaged, and labeled trial supplies must be delivered to many sites in many countries which have diverse regulatory requirements. Some ideas for optimizing the procedures for getting the appropriate information, planning, and executing the proper logistics, accommodating varying national cultures, and meeting the technical and compliance needs for the product will be presented.

In Japan, until about 10 years ago, clinical trials were conducted in public hospitals and/or hospitals affiliated with medical schools. During that period, written informed consent was not necessary in order to carry out clinical trials. The new Good Clinical Practices created major changes for physicians, including the increase in patients' rights and the requirement for written informed consent. Institutional review boards were established at hospitals to ensure that clinical trials are performed ethically. Standard operating procedures based on Good Clinical Practices requirements were created. In order to conduct clinical trials promptly at the Cardiovascular Hospital of Central Japan, clinical research coordinators were introduced. At present, our rate of patient enrollment is fairly high compared to hospitals affiliated with medical schools. Trained clinical research coordinators have played a key role in obtaining written informed consent.

Enforcement of the new Good Clinical Practices enacted in response to introduction of the International Conference on Harmonization guidelines has brought about dramatic changes in clinical trials in Japan. The participation of private clinics is not yet permitted because of difficulty in handling adverse events, but it is expected that private clinics will eventually participate in clinical trials. This article describes a clinical trial system established at Togane Hospital. The system includes a clinical trial network that assists physicians who participate in clinical trials. To improve trial quality, we plan to introduce clinical research coordinators into private clinics, and to create an electronic case report form. Because we use the Internet for a variety of processes, including data collection and transmission, this system was designed as a virtual private network to ensure the consistency and security of data. The regional core public hospital functions as a site management organization in this network and supports the private clinics. The network aims to contribute to the improvement of regional medical care, and may be extended to clinical epidemiology to help develop evidence-based medicine in Japan.

A global Investigational New Drug (IND) Clinical Studies Task Force was established in 1999 by the Johnson & Johnson Pharmaceuticals Group with representation from The R. W. Johnson Pharmaceutical Reseach Institute, The Janssen Research Foundation, and several Janssen-Cilag operating companies. This task force was charged with evaluating the need for the conduct of global clinical trials in accordance with the United States IND as prescribed by Part 312 in Chapter 21 of the United States Code of Federal Regulations in order for such trials to be accepted by the Food and Drug Administration (FDA) in support of a regulatory submission. The task force recommends that global product teams consider the possibility of conducting clinical studies under the United States IND, wherever possible, in establishing product development strategies. While there are distinct advantages to conducting clinical trials under the IND, the task force points out that the responsibilities incurred can be a challenge globally in terms of administrative oversight, adequate internal resources, and continuous training on United States IND requirements for internal and clinical trial center personnel. Therefore, the task force advises that these factors be evaluated by the global product teams and recognizes that it may not be appropriate for all clinical trials to be conducted under the IND. Whether or not the global product team decides to conduct pivotal trials under the IND, it is essential that all clinical trials be conducted in accordance with Good Clinical Practice (GCP) standards as outlined by the International Conference on Harmonization (ICH) to ensure their acceptance by regulatory authorities worldwide. The IND Clinical Studies Task Force urges global product teams to include up-front dialogue with the FDA on development strategies. This is especially important when clinical study centers outside the United States are not filed to the IND. Dialogue with FDA is critical to the selection of clinical study centers on a geographic basis and the definition of systems used for the monitoring of all study sites as well as for the collection, analysis, and communication of safety information on a global basis throughout the conduct of global clinical trials.

The safe and effective use of pharmaceuticals often depends on patients' understanding the drug's risks, benefits, and directions for use. This information is often communicated in printed materials. However, limits on the patient's willingness and ability to process this information make communications problematic. We review how patients process written information. We postulate that processing drug information is similar to drug pharmacokinetics. It is not the information presented to a patient that matters, rather it is the interaction of the patient with the materials that determines the nature and amount of information communicated.

Increasing use of dietary supplements in the United States has commanded attention to regulatory issues regarding these products. Prior to the Dietary Supplement Health and Education Act of 1994 (DSHEA), regulation of dietary supplements was a gray area—they were classified somewhere between food and drugs. Regulations governing the acceptable claims for dietary supplements were finalized in January 2000, yet many issues remain controversial concerning the questionable safety and efficacy of these products. Premarketing approval based upon clinical trials is not required for dietary supplements, making it difficult to determine safety, efficacy, and potential drug interactions. Little is known about the use of dietary supplements in pregnancy or in pediatric populations. Many supplements do not have standards for quality, strength, and purity. These concerns, as well as others, must be addressed in order to provide patients with safe and effective dietary supplements that could be instrumental in preventing disease and promoting health.

Recent developments in consumer access to drug information are reviewed. Technological changes, federal regulatory developments and changes in physician and pharmacist practices resulting from health care cost containment strategies, and changes in pharmaceutical industry practices toward providing drug information to consumers are highlighted and discussed. The resulting changes in the ability of consumers to make informed choices concerning health care and to make sound decisions in the use of prescription drugs are described. The role of the pharmaceutical company drug information department as a part of this process is critically evaluated.

Medical affairs groups are an increasingly vital part of the modern pharmaceutical company. This review will highlight the major functions, customary organizational structure, and responsibilities of medical affairs departments. These groups perform a wide range of activities often overlapping with sales, marketing, clinical development, and customer service. Medical affairs personnel must strive for the highest scientific integrity in order to produce successful clinical trials and provide the greatest support for the market. It is important that they well understand the regulations surrounding their activities and appreciate the commercial implications of their work. How well the medical affairs group maintains this delicate balance will determine its overall success.

The 1999 Washington Legal Foundation (WLF) decision stated that the Food and Drug Administration (FDA) was in violation of the pharmaceutical/biotechnology industry's right to commercial free speech by unduly limiting its ability to distribute truthful, nonmisleading information about off-label uses of its products. The objective of this survey was to assess pharmaceutical companies' current practices for distributing peer-reviewed journal article reprints relating to off-label uses for their medications in response to the 1999 district court's judgment in favor of the WLF. Respondents were employees in the medical information departments of 27 pharmaceutical/biotechnology companies, 5 of which were unable to provide information. Seventy-three percent (16/22) of the companies that participated in the survey were either distributing articles at the time of the survey or were planning to distribute articles under the WLF ruling. The sales force carried the responsibility for distribution at 94% (15/16) of the companies surveyed. Seventy-five percent (12/16) of the companies surveyed affixed disclaimers to the articles that highlight the off-label nature of the described disorder and/or disclose the company's interest in the product.

Technical product information found on the Web sites of most pharmaceutical companies is limited to the package insert. In an effort to give health care professionals expanded access to technical information, the Professional Product Information department at Roche Laboratories Inc. created a Web site that provides a broad variety of drug information, including on- and off-label information on products marketed by Roche. The Professional Product Information Web site is designed to provide clinicians with the same information that would otherwise be provided in response to a telephone call or a written inquiry. The development of this Web site required the collaboration of several departments including law, regulatory affairs, technology management, business information systems, and media design management. This article reviews the many considerations in creating such a Web site.

Despite the fact that prescription drugs are an increasingly important component of modern health care, especially for the elderly and disabled populations suffering from chronic conditions, 35% of Medicare beneficiaries lack any form of prescription drug insurance. Congress is currently debating six major proposals to extend insurance protection to outpatient prescription drugs under Medicare. Five of these proposals suggest the use of pharmacy benefit managers (PBMs) to improve the cost-effectiveness of the prescription drug benefit.

A Tufts Center for the Study of Drug Development (Tufts CSDD) survey of eight leading PBMs shows that during the last five years PBMs have increased their enrollment of Medicare beneficiaries considerably. PBMs currently facilitate moderate to full access to pharmaceuticals for approximately 20% of Medicare beneficiaries. Seven of the eight PBMs surveyed are also developing disease management programs targeted specifically at the Medicare population. However, regarding the feasibility of a universal prescription drug benefit, a number of issues concerning how to structure government contracts with PBMs and how to meet certain political challenges to PBM mediation remain unresolved.

When evaluating a new diagnostic test against a less than perfect “gold standard,” the kappa coefficient of agreement κ is often inappropriately used as a measure of “diagnostic accuracy,” which frequently leads to paradoxical findings. In this paper, κ is expressed as a function of disease prevalence and diagnostic accuracy (subject to Youden's index > 0), whereby necessary and sufficient conditions, given the accuracy rates, are derived to aid in locating the maximizer of κ. Paradoxical behavior of κ can thus be detected in the light of diagnostic accuracy. Attempts are made to clarify the subtle difference between “diagnostic accuracy” and “diagnostic reliability.” The implication of this difference is then assessed from a regulatory perspective. In order to extend the idea of κ beyond its originally intended use, the maximum likelihood method, coupled with the Expectation-Maximization algorithm, is proposed as a remedial option, not for measuring diagnostic agreement or reliability but, rather, for evaluating diagnostic accuracy. Some illustrative examples adapted from published data are provided.

Several reasons account for the delayed development of fixed combination antihypertensive drugs in Japan. First, specialists have not wanted to lose their flexibility in combining individual antihypertensive drugs. Second, officials of the Ministry of Health and Welfare, Japan, have hesitated to approve combinations of a given pair of drugs from the many drugs available within the same category. Third, concrete guidelines for the clinical evaluation of fixed combination antihypertensive drugs have never been implemented. However, an opinion survey and the results of prospective postmarketing surveillance on antihypertensive drugs indicate that the efficacy and advantages of combination therapy for hypertension are well recognized by Japanese physicians. A negative balance of the National Health Insurance budget, which requires the improved cost-effectiveness of drug treatment, and new guidelines for the evaluation of antihypertensive drugs, which will be implemented in conjunction with the International Conference on Harmonization guidelines, may promote the development of fixed combination products in the near future.

In clinical trials, generally only about half of unselected patients with mild to moderate hypertension respond to treatment with antihypertensive monotherapy. In clinical practice, only about a quarter of hypertensive patients actually achieve the desired target blood pressure levels. Fixed-dose combination antihypertensive therapy is thus important in order both to increase the proportion of patients in whom blood pressure control is achievable and to simplify treatment regimens, thus contributing to improved patient compliance and hence improved blood pressure control in community practice.

Fixed-dose antihypertensive combination products have been available for many years, but even in the early 1980s they were not universally accepted in academia. Recognition of the importance of combination products for the treatment of hypertension has increased during the last two decades in both the United States and Europe. Such recognition is likely to increase further as clinical consensus guidelines establish increasingly ambitious targets for blood pressure control and as global efforts increase to implement such guidelines into general practice.

There are similarities and some differences between the United States and Europe both in clinical guidelines for the treatment of hypertension and in regulatory requirements for the development of fixed-dose antihypertensive combination products. The regulatory requirements of both regions require that the two (or more) components of a combination product must be shown to contribute to its effect. However, available information suggests that compliance with European Union (EU) guidelines requires more extensive clinical evaluation than compliance with United States Food and Drug Administration (FDA) recommendations.

The increased development costs of bringing new drugs to the market is one of the main reasons for pharmaceutical companies to globalize their operations. Globalized pharmaceutical businesses require their international operations to be present in all major markets. The various subsidiaries and affiliates operate under quite different cultures and guidelines. In the absence of effective communication and teamwork, misunderstanding can easily arise and valuable synergies are lost, resulting in suboptimal customer service and product support. This paper describes a European medical and scientific managers' network in which international meetings address activities, roles, and goals for the individual managers. By regular face-to-face contact joint decision making builds trust and team spirit. Internally, value can be assessed by the enthusiasm, willingness to participate in meetings, and commitment of all team members. Externally, effectiveness is revealed by product support, rapid growth, market penetration, and attainment of targets.

High-quality starting materials for medicinal products are essential to the high quality of finished products. In 1995 and 1996 adulterated glycerin caused acute renal failure and subsequently death of about 88 children in Haiti. This case is discussed with respect to risk detection and analysis in the manufacture, distribution, and trade of active as well as nonactive starting materials. Parties involved are not sufficiently aware of the risks. Overall, there is lack of transparency. There is strong need for a Good Trading Practice. Recommendations to health authorities conclude this brief overview.

In the United Kingdom, the Home Office regulates the use of animals for experimental and other scientific purposes. Applicants must satisfy the regulatory authority that the animal use is justified and scientifically sound, and that the specific objectives cannot be realized by methods not requiring the use of living animals, or by protocols and endpoints likely to cause less animal suffering. Once granted, project license authorities remain valid for up to five years. In the context of species selection for preclinical safety testing, applicants must make transparent the principles and practices that will be used to select the most relevant species, and the most appropriate and refined plans of work and protocols.

India has an ancient heritage of traditional medicine. The materia medica of India provides a great deal of information on the folklore practices and traditional aspects of therapeutically important natural products. Indian traditional medicine is based on various systems including Ayurveda, Siddha, and Unani. The evaluation of these drugs is primarily based on phytochemical, pharmacological, and allied approaches including various instrumental techniques such as chromatography, microscopy, and others. These traditional systems of Indian medicine are each unique but there is a common thread in their fundamental principles and practices. With the emerging worldwide interest in adopting and studying traditional systems and exploiting their potential based on different health care systems, the evaluation of the rich heritage of traditional medicine is essential. The government and the private sector are exploring all of the possibilities for the perfect evaluation of these systems in order to effectively adopt the therapeutic approaches available in original systems of medicine as well as to help in generating data to put these products on the national health program.

Estimates of 100000 Americans dying of ‘medication errors’ each year have caught the popular imagination … and they might even be true. Psychologists regard errors as defects in intentional acts. They distinguish between ‘mistakes’—errors in planning the act, and ‘slips of action’ or ‘lapses of memory’—errors in executing the act. Both sorts of error are important in prescribing and giving medicines. Can we do anything to make the process of prescribing and giving medicines safer? We undoubtedly can, and the changes that are needed start with the manufacturer and end with the patient. Drugs can be designed to be safe and easily distinguished one from another. The prescribing environment can be made safer by ensuring that difficult work (printing drug names, checking for interactions, avoiding major dosage errors) is done by computer. We should also recruit patients to help us to treat them safely. Others have designed safety into their systems, and we should seek to do the same for prescribing and giving medicines.