The biotechnology innovation machine: a source of intelligent biopharmaceuticals for the pharma industry--mapping biotechnology's success.

The marriage of biotechnology and the pharmaceutical industry (pharma) is predicated on an evolution in technology and product innovation. It has come as a result of advances in both the science and the business practices of the biotechnology sector in the past 30 years. Biotechnology products can be thought of as "intelligent pharmaceuticals," in that they often provide novel mechanisms of action, new approaches to disease control, higher clinical success rates, improved patient care, extended patent protection, and a significant likelihood of reimbursement. Although the first biotechnology product, insulin, was approved just 32 years ago in 1982, today there are more than 200 biotechnology products commercially available. Research has expanded to include more than 900 biotechnology products in clinical trials. Pharma is substantially engaged in both the clinical development of these products and their commercialization.

A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials.

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Reinventing bioinnovation.

The landscape for bioinnovation is undergoing a seismic shift as drug developers, regulators, academic institutions, and government research organizations adapt to the formidable challenge of bringing new medicines to market. The inability to translate current advances in the scientific understanding of disease into new therapeutics is forcing all sectors to replace traditional drug development paradigms with newer and more efficient models. This issue of Clinical Pharmacology & Therapeutics explores these changes to the bioinnovation ecosystem.

FDA review divisions: performance levels and the impact on drug sponsors.

Sponsors of new drug applications (NDAs) confront a host of uncertainties, one of the more vexing of which is negotiating the differing and inconsistent policies and standards among the various US Food and Drug Administration (FDA) drug review divisions. The FDA faces many challenges as well, internal and external, that confound its efforts to provide a consistent and timely review process. In this article, we examine various input factors, such as the number of regulatory filings, that contribute to fluctuations in the annual FDA workload, as well as output factors, such as NDA approval times, that are often viewed by sponsors as measures of the FDA's performance. Interdivisional differences at the FDA, in both input and output factors as well as other process-related factors, such as issuance of complete response letters, division staff levels, and quality of the sponsor's application, are considered in light of their contribution to the vagaries of the sponsors' experiences with the regulatory process.

Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009.

The first decade of the 21st century was a challenging period for the pharma sector and could prove to be a turning point in the evolution of the industry. We examine drug development performance metrics for new product approvals during 2000-2009 and compare them with those of the prior two decades. The results indicate that, whereas total approvals are currently at a 25-year low, the percentage of priority products is nearly 50% of the total--a 30-year high. Following enactment of the Prescription Drug Use Fee Act of 1992 (PDUFA), the mean duration of the approval phases of drug development declined by more than 1 year over the 30-year period--to a low of 1.2 years in 2005-2009--whereas the duration of the clinical phases increased. The longer clinical phases were due, in part, to a greater number of approved central nervous system (CNS) and antineoplastic agents, two therapeutic classes with relatively long average development times (8.1 and 6.9 years, respectively). The results provide the underpinnings of a fundamental shift in the structure of the research-based industry.

Impact of the new US health-care-reform legislation on the pharmaceutical industry: who are the real winners?

Over the past two years, the US pharmaceutical and biotechnology industries were preparing themselves for passage of some type of health-reform legislation with a clear appreciation-and concern-about the enormous impact any law would be likely to have on the structure and viability of the research-based industry. Now, with final passage in March 2010 of the Patient Protection and Affordable Care Act and its companion "quick-fix" and budget bill, the Health Care and Education Reconciliation Act, it is a good time to take a look at how the industry fared and assess how the various provisions of the health-care reform bill might affect the industry's long-term prosperity and growth.

New drug approval times and 'therapeutic potential' in Canada, Australia, Sweden and the United States during the period 1992 to 1998.

In two previous studies, the times required to approve new drugs in Canada, Australia, Sweden, the United Kingdom and the United States during the periods 1992 to 1995 and 1996 to 1998 were compared. However, during each of these two periods, only a fraction of the drugs that were approved in any of the countries were approved in all of them. Because an analysis based solely on drugs approved in all the countries would provide additional information, data from the previous studies have been used to compare drugs approved in each of Canada, Australia, Sweden and the United States during the period 1992 to 1998. In addition, applications that received a 'priority' or a 'standard' review by the United States Food and Drug Administration were analyzed separately to determine whether differences between the countries diminished for drugs considered to be of potentially greater therapeutic value. For the 87 drugs identified as being approved for marketing in all four countries during the period 1992 to 1998, approval times in Canada and Australia were not significantly different, but both Canada and Australia had significantly longer times than those of the United States and Sweden (P<0.001). Of the 87 drugs, 37 (43%) received a priority review in the United States. In both the priority and standard review categories, the Australian and Canadian median approval times were significantly longer than those in Sweden and the United States. The results demonstrate that, in general, both priority and standard new drug applications are reviewed more expeditiously in Sweden and the United States than in Canada. Canadian patients continue to experience delayed access to potentially valuable medicines.

The prescription Drug User Fee Act of 1992 and the new drug development process.

The Prescription Drug User Fee Act of 1992 (PDUFA) authorizes the US Food and Drug Administration (FDA) to levy user fees on manufacturers who submit applications to the agency. Revenues are dedicated to the achievement of a set of specific performance goals, documented by the FDA Commissioner and referenced in the Act. The FDA currently credits PDUFA with the agency's success in reducing new drug review times and eliminating the formidable new drug application (NDA) backlog. To provide an independent assessment of PDUFA's impact on the new drug development process, the Tufts Center for the Study of Drug Development established an annual user fee survey of over 50 major pharmaceutical and biotechnology firms with operations in the United States. As of December 31, 1996, survey data have been collected for fiscal years 1994, 1995, and 1996. Data from a cohort of user fee drugs approved in 1993-1996 were compared with data from all non-user fee drugs approved in 1990-1992. Whereas the mean approval phase (NDA submission to approval) for the user fee drugs was considerably shorter than that for the non-user fee drugs (14.5 versus 31.0 months, respectively), the mean clinical phase (investigational new drug application filing to NDA submission) was somewhat longer (88.0 versus 81.1 months, respectively). As a result, the total time from the start of clinical testing to drug approval (total phase) was only marginally shorter for the user fee drugs (102.0 versus 112.1 months, respectively). These results highlight the need for efforts to reduce lengthy drug development times.

The new drug approvals of 1993, 1994, and 1995: trends in drug development.

Growing concern within Congress, the pharmaceutical industry, and the Food and Drug Administration (FDA) over the excessive time and cost required to develop new drugs and bring them to market has led to several initiatives designed to speed the drug development process, e.g., the Prescription Drug User Fee Act of 1992 and recent efforts at legislative reform of the agency. To assess the impact of these initiatives, it is useful to examine recent trends in new drug development and review. This report is the fourth in a series in which we analyze new chemical entities (NCEs) recently approved by the FDA. In 1993, 1994, and 1995, the FDA approved 75 new drugs, 67 of which met the Tufts Center's definition of an NCE. Of the 67, 31 (46%) received priority review, 13 (19%) had orphan drug status, and 5 (7%) were approved under the accelerated approval regulations. For the 67 NCEs, the mean length of the clinical phase (investigational new drug filing to new drug application submission) was 7.1 years, and the approval phase (new drug application submission to approval) was 2.0 years. The mean approval phase for the 31 priority NCEs (1.5 years) was 38% shorter than that for the 36 standard NCEs (2.5 years). Compared with similar values for the previous 3-year period, the mean clinical phase for all NCEs increased by 16%, whereas the mean approval phase decreased by 23%. Of the 66 NCEs for which foreign marketing data were available, 34 (52%) were available in foreign markets one or more years prior to U.S. approval, with a mean of 7.7 years of earlier foreign marketing.

The Prescription Drug User Fee Act of 1992. A 5-year experiment for industry and the FDA.

The Prescription Drug User Fee Act of 1992 authorises the US Food and Drug Administration (FDA) to collect in excess of $US332 million in user fee revenues over a 5-year period. Not only did Congress determine that the revenues would be dedicated to expediting the FDA's review of human drug applications, the FDA articulated formidable time-specific performance goals to be achieved by fiscal year 1997. At the mid-point in the 5-year programme, the FDA reported that it had met or exceeded its performance goals. In this article, we review the history of the user fee scheme in the US, outline the details of the legislative provisions, and discuss the challenges confronting the agency as it works to simultaneously meet the user fee goals and respond to political forces calling for substantive FDA reform. User fees loom large for the global pharmaceutical and biotechnology industries as economic pressures force a number of countries to consider shifting a portion of the cost of regulatory review to the regulated industry. This article provides a reference on the US framework and may be useful in future international comparisons as the user fee phenomenon spreads.

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

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.

The new drug approvals of 1990, 1991, and 1992: trends in drug development.

Efforts to speed the development and review of new drugs have increased sharply in recent years. This report, which is the third in a series on trends in drug development, examines the new drug approvals of 1990, 1991, and 1992. During the 3-year study period, the Food and Drug Administration (FDA) approved 79 new drugs, 74 of which met the Center for the Study of Drug Development's definition of a new chemical entity (NCE). Of the 74 NCEs, 36 (49%) were considered by the FDA to represent notable therapeutic gains and were selected for "priority" review (i.e., drugs rated 1P, 1A, 1AA, and 1B), and 38 (51%) were considered to represent little or no gain and received "standard" reviews (i.e., drugs rated 1S and 1C). Investigational new drug application (IND) filing and new drug application (NDA) submission dates on all 74 drugs were obtained from responses to our manufacturer surveys as well as from FDA and public sources. The mean length of the clinical phase (IND filing to NDA submission) was 6.1 years and that of the review phase (NDA submission to approval) was 2.6 years. Of the 74 NCEs, 43 (58%) were available in foreign markets at least 1 year before U.S. approval, with a mean of 5.6 years of foreign marketing. In general, 1990 to 1992 figures are similar to those in the last half of the 1980s.

The role of the research-based pharmaceutical industry in medical progress in the United States.

The development of innovative new drugs is a time-consuming, expensive, and risky process. Despite these challenges, the pharmaceutical industry has been remarkably successful in developing a broad range of important new medicines. This report examines several aspects of new drug development in the pharmaceutical industry and provides a quantitative evaluation of the role of the drug industry in medical progress. Results indicate that of the 196 new chemical entities approved by the FDA from 1981 through 1990, the source of 92% was the pharmaceutical industry. Within the industry, there was a sizeable increase in the level of clinical research activity (based on the number of investigational new drug [IND] filings) from the mid-1970s to the mid-1980s; moreover, for U.S.-owned firms IND filings increased 46% between 1976 and 1989. Analysis by therapeutic category indicates that much of this clinical research activity was directed towards the development of drugs for cardiovascular disease and mental illness, and more recently towards the treatment of cancer and acquired immunodeficiency syndrome (AIDS). These represent therapeutic areas in which there is an urgent need for new and more effective medicines. The high level of research activity was also reflected in the relative number of drug approvals in these areas. It is hoped that the present findings will contribute to the current debate on drug policy issues and encourage policy-makers to consider what impact proposed health care policies might have on pharmaceutical innovation.

Pharmaceutical regulation in the European Community: barriers to single market integration.

The European Community (EC) plans to create a single market for pharmaceutical medicines, but the drug industry is closely linked to cultural and societal values concerning health; to the national regulatory agencies responsible for the evaluation of safety, quality, and efficacy of new drugs; to multinational and domestic companies competing in national and international markets; and to varied interest groups of professionals and consumers organized along national and multinational lines. We review the history of the EC's policy proposals, examine reactions from all these interested parties, and assess the prospects for integration into a single market. The contentious debate that continues among the parties over national prerogatives, industrial interests, professional mandates, and consumer concerns clouds the prospects for a system of centralized drug registration that will be acceptable to all EC member states.

New indications for already-approved drugs: an analysis of regulatory review times.

A survey of the U.S. pharmaceutical industry was conducted to obtain data on the length of the review process for supplemental indications of already-approved new chemical entities (NCEs). Responses were received from 51 firms and covered supplemental indications of 348 NCEs that were approved during 1963 to 1988. Since extensive toxicity and safety evaluation would generally not be required for supplemental indication reviews, one would expect supplemental indications, on average, to be reviewed more quickly than applications for the associated original indications. The mean +/- standard deviation review time for the 172 supplemental indications in the sample is 21.5 +/- 18 months; the average review time for the associated 94 original indications is 23.5 +/- 18 months. The difference in average review times is not statistically significant. Analysis of review times for indications grouped by Food and Drug Administration (FDA) reviewing division showed a statistically significant difference between supplemental and associated original indication review times only in the cardio-renal division. In that division, average review times were longer for supplemental indications (25.6 vs. 19.3 mo; P less than .05). Analysis of time trends showed a significant increase in average supplemental indication review time for 1985 to 1988 approvals relative to the average associated original indication review time (P less than .01) and to average supplemental indication review time for earlier time periods (P less than .01). These results suggest the need for a close examination of the supplemental indication review policy of the FDA.

The new drug approvals of 1987, 1988, and 1989: trends in drug development.

The new drug approvals of 1987, 1988, and 1989 were analyzed to determine whether there are any emerging trends in the US drug development and review processes. Sixty-four new drugs were approved by the FDA during this period, of which 55 met the Center for the Study of Drug Development's definition of a new chemical entity (NEC). For the 55 NCEs, the mean length of the investigational new drug application (IND) phase (IND filing to NDA submission) was 5.2 years, the new drug application (NDA) phase (NDA submission to approval) was 2.9 years, and the total phase (IND filing to NDA approval) was 8.1 years. Nine of the 55 NCEs were classified by the FDA as 1A (important therapeutic gain), 15 were classified as 1B (modest gain), 29 were classified as 1C (little or no gain), and 2 were classified as 1AA (drugs to treat AIDS and AIDS-related conditions); 10 drugs were granted orphan status. The mean NDA phase for 1A drugs was 2.4 years; 1B drugs, 2.9 years; 1C drugs, 3.1 years; 1AA drugs, 1.4 years; and orphan drugs, 2.5 years. Forty-four of the 55 NCEs (80%) were available in foreign markets before US approval was given, with a mean of 6.5 years of prior marketing. These data are consistent with figures for previous years and suggest little change in the rate of new drug development and review in the United States.