Showing papers by "Tufts Center for the Study of Drug Development published in 1995"

Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: A regulatory perspective

Abstract: The objective of the present study was to compare the number of new chemical entities (NCEs) and new biologicals entities (NBEs) approved for marketing during the period 1974 through 1993 in the United Kingdom, the United States, and Spain that were subsequently discontinued (removed from the market, withdrawn, or whose license was allowed to lapse) while a question of safety existed. Of the products approved during the two decades of the study period, a total of 29 drugs were subsequently discontinued for safety reasons in at least one of the three countries (United Kingdom: 20 safety discontinuations; United States: 10; and Spain: 16). These represent 3% to 4% of all drugs introduced in these countries, an increase compared to the period from 1964 through 1983, when approximately 2% of all NCEs were discontinued for safety reasons. The therapeutic classes most commonly associated with safety discontinuations were the nonsteroidal anti-inflammatory drugs (nine drugs), vasodilators (four drugs), and antidepressants (three drugs). U.S. companies or their foreign subsidiaries were involved as originators (patent-holders and/or developers) of approximately 40% of the drugs discontinued for safety reasons.

Research and development costs for new drugs by therapeutic category. A study of the US pharmaceutical industry.

Abstract: The clinical period (i.e. clinical trial and long term animal testing) development costs of a random sample of new chemical entities (NCEs) were examined for differences in average cost. All of the NCEs studied were first tested in humans between 1970 and 1982, and were classified for the purposes of the study by therapeutic class. The costs of unsuccessful projects were included with those of projects that resulted in US marketing approval. Including income forgone from expending funds before returns are earned (‘time costs’), the capitalised (i.e. out-of-pocket plus time) clinical period costs per approved NCE were $US70, $US98, $USI03 and $US163 million (1993 dollars) for anti-infective, cardiovascular, neuropharmacological and nonsteroidal anti-inflammatory drugs, respectively. Combining the data for all therapeutic categories, the mean clinical period cost per approved NCE was $US93 million. Omitting costs associated with unsuccessful projects, the mean capitalised clinical period costs for approved NCEs ranged from $US7.1 million (for topical steroids) to $US66.7 million (for cardiovascular agents) [ 1993 dollars ]. The estimates of total clinical period costs per approved NCE depend on average out-of-pocket clinical phase costs, attrition rates across phases (i.e. the rates at which compounds drop out of active testing), the probability of marketing approval and deve lopment and regulatory review times. Phase attrition and approval rates are the most imponant sources of variability in total clinical period costs between therapeutic categories. Development cost estimates by therapeutic category did not correlate strongly with US sales in the fifth year of marketing. Cardiovascular NCEs had much higher than average sales revenues but clinical development costs for these drugs were only slightly above average. Conversely, nonsteroidal anti-inflammatory drugs attained average sales revenues but had much higher than average development costs.

R&d Costs, Innovative Output and Firm Size in the Pharmaceutical Industry

Abstract: This study examines the relationships between firm size, R&D costs and output in the pharmaceutical industry. Project–level data from a survey of 12 US–owned pharmaceutical firms on drug development costs, development phase lengths and failure rates are used to determine estimates of the R&D cost of new drug development by firm size. Firms in the sample are grouped into three size categories, according to their pharmaceutical sales at the beginning of the study period. The R&D cost per new drug approved in the US is shown to decrease with firm size, while sales per new drug approved are shown to increase markedly with firm size. Sales distributions are highly skewed and suggest that firms need to search for blockbuster drugs with above–average returns. The results are consistent with substantial economies of scale in pharmaceutical R&D, particularly at the discovery and preclinical development phases.

Trends in Drug Development Costs, Times, and Risks:

Abstract: NEW DRUG DEVELOPMENT in the United States has been characterized by long development and regulatory review periods, high costs, and substantial scientific and financial risks. The factors that explain why the development and regulatory review processes are lengthy, costly, and risky are complex and vary in relative importance over time. Gathering reliable data on these processes and analyzing those data should precede and enhance evaluations of the factors that affect new drug development and regulatory review. This section surveys literature on the cost of drug development, the lengths of the development and regulatory review phases, and technical risks in new drug development for new chemical entities (NCEs). New results on clinical cost and clinical trial complexity for recent years are also presented. tures grew at about a 10% compound annual rate since 1979. On the other hand, new drug approvals in the United States have not yet increased at anywhere near such a rate. Without doubt, there is a substantial lag between R&D expenditures and marketing approval. Most of the expenditures at the end of the period shown should be associated with approvals in the future. Even so, it is hard not to at least suspect, and at most conclude, that R&D costs have increased over time. Several studies have averted the problems inherent in associating industry-level R&D expenditures with NCE approvals by estimating the cost of new drug development using detailed disaggregated data. Figure 2 shows comparative preclinical, clinical, and total costs per approved selforiginated NCE from two studies (1,2).*

A Drug Lag Update

Abstract: IN THE MID-l970s, Wardell’s pioneering drug lag studies revealed a therapeutically significant delay in the introduction of new drugs in the United States compared with the United Kingdom ( 1,2). These and later studies by other investigators demonstrated that the United States consistently lagged behind other industrialized countries in both the rate and timing of new drug introductions. Moreover, the impact of this delay on therapeutic practice in the United States was not offset by a significantly better safety record. Based on these findings, Wardell (3) concluded that the United Kingdom benefited from its less restrictive policies for approving new drugs and from its more developed program of postmarketing surveillance. At Congressional hearings in 1979, Wardell stated: “There is little doubt that for marketed drugs and approved therapeutic indications, the United States lags greatly, in the sense that new drugs are usually available abroad either exclusively or much earlier, and for a wider range of indications” (4). Although initially rejected by the FDA (5,6), the drug lag concept was eventually accepted as fact by policymakers in Concurrently focused on other concerns, such as health care reform, cost containment, and international competitiveness. Moreover, current efforts to standardize international regulatory practices for pharmaceuticals (eg, through the International Conference on Harmonization) and the increased globalization of the drug industry suggest that disparities among countries in the timing and rate of new drug introductions will eventually diminish. Nonetheless, recent reports in the academic literature and the lay press suggest that the drug lag continues to be a critical issue and that delays persist in the availability of important new therapies in the United States. In this report, the current status of the drug lag is examined. The first section reviews studies by the Tufts Center for the Study of Drug Development (CSDD) that show that the United States continues to lag behind other countries in the introduction of new pharmaceutical products. The next section examines recent data focusing on several specific therapeutic areas. The final section assesses the therapeutic implications of the drug lag.

Availability of anticancer drugs in the United States, Europe, and Japan from 1960 through 1991

Abstract: Clinical Pharmacology & Therapeutics (1995) 58, 243–256; doi:

Studies and Inquiries into the FDA Regulatory Process: An Historical Review:

Abstract: THE FOOD AND DRUG Administration (FDA) has been dubbed “the most closely watched federal regulatory agency in existence” ( 1 ), and its regulatory activities “the most thoroughly investigated and studied program of government regulation in history” (2). The many investigations and inquiries have produced what has been described as a “virtual tidal wave of recommendations” (3). The validity of these comments becomes readily apparent even on cursory review. For the purposes of this White Paper, a detailed review and documentation of a substantial portion of this investigatory activity has been undertaken. The first section of this segment of the White Paper draws from a comprehensive two-part summary prepared by Peter Barton Hutt in which he provides an historical review of investigations and reports of FDA regulation over the years 1822-1983. All inquiries, congressional hearings, commissions, studies, and other reports concluded during that period are listed in the appendix to this article. They have been organized into six broad categories according to the nature of the event or concern that triggered the inquiry: drug safety, ethical issues, FDA administration and resources, advisory committees, FDA review process, and competitiveness issues. A summary statement of the recommendations or conclusions of each inquiry is also provided. In the next two sections, the recommendations of the major inquiries undertaken during the periods 1981-1987 and 19881992, respectively, are reviewed in detail. Regulatory and administrative changes that, at least in part, appeared to occur in response to repeated criticisms or recommendations for reform over the years are also reported. Since similar proposals often arose from diverse sources, it is usually impossible to say that a specific inquiry or commission provided the sole impetus for any particular reform. When examined in their entirety, the recommendations reported in the first three sections below project a drumbeat quality with certain issues and themes appearing repeatedly. The last section reflects on the energy and efforts directed to improving the efficiency of drug development and the FDA process, and provides a summary of the

Improving the drug development process: needed reforms

Abstract: MODERN DRUG DEVELOPMENT has entered a critical phase in its history as the result of a variety of forces impinging on the pharmaceutical industry. These forces include pressures for cost containment, plans for international harmonization of regulatory standards, the impact of user fee legislation, and the urgent demands of patient advocates for new remedies for currently untreatable diseases. All of these factors have created a situation where, for the first time, both the regulators and the regulated must work together to make the process of drug development more efficient, speedier, and less costly, while continuing to protect the public from preventable toxicity and flawed products. As part of the user fee legislation, Commissioner Kessler set ambitious goals for his agency with regard to the elimination of backlog applications and prompt action on new drug applications (NDAs). These quotas can be met by refusing to file NDAs, rejecting them after filing, or encouraging sponsors to withdraw applications, but eventually Congress will contrast such actions with the intent of the legislation the speedier approval of new medicines. While it has been common to look upon the phase of NDA review as that part of drug development primarily under the influence of FDA, this posture is wrong on two counts: on the one hand, the phase is unquestionably affected by the quality of the NDA and the promptness and quality of sponsor response to FDA questions and concerns; on the other hand, that part of the development process before NDA filing is affected significantly not only by the sponsor’s anticipation of FDA demands, but also by the extent and nature of FDAsponsor interaction from before IND filing until NDA filing. The logical consequence of all of the above is that the extremely lengthy and expensive process of drug development can best be shortened and made more efficient by early, frequent, and continuing collegial discussions and joint planning involving industrial and regulatory scientists so that (barring unforeseen problems) the development strategy, application format, and data needs are agreed to in advance. With such an effort, an NDA would become essentially “self-reviewing” and would not suffer from avoidable delays.