* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Regulatory Considerations in the Post-Vioxx Era
Neuropsychopharmacology wikipedia , lookup
Epinephrine autoinjector wikipedia , lookup
Discovery and development of non-nucleoside reverse-transcriptase inhibitors wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Pharmaceutical marketing wikipedia , lookup
Psychopharmacology wikipedia , lookup
Drug design wikipedia , lookup
Orphan drug wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Theralizumab wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug interaction wikipedia , lookup
Compounding wikipedia , lookup
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
List of off-label promotion pharmaceutical settlements wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Regulatory Considerations in the Post-Vioxx Era By Julia S. Rivers, MA 18 December 2009 The US environment for drug development and registration has evolved as a result of many significant and public events that span the course of the past century. In the early 1900s, public outcry following the exposure of deplorable conditions in meat packing plants and false claims about patented medicines prompted enactment of the Pure Food and Drug Act of 1906. This federal law ultimately provided the foundation for what is now the Food and Drug Administration (FDA). In the 1930s, public awareness of the need for greater federal regulation of drug safety resulted from the sale of a poisonous elixir formulation of sulfanilamide: this national tragedy prompted Congress to pass the Federal Food, Drug, and Cosmetic Act of 1938, which required premarket demonstration of a new drug’s safety. The 1960s brought a similar public health scare when evidence of the teratologic effects of thalidomide became known. Although never approved for use in the US, thalidomide was available for use in some other countries and was being studied in the US. The Kefauver-Harris Amendments were subsequently passed by Congress, requiring premarket evidence of efficacy and safety of all new drugs, both prescription and OTC, and requiring adverse reaction reporting for the first time in US history. In the early part of the 21st century, another significant set of circumstances again led to increased public awareness about the safety of pharmaceutical products. Media, Congress, consumer advocates, watchdog groups and the pharmaceutical industry were engaged in dialogue. Would the existing drug development and FDA approval process prove to be sufficient to maintain public confidence in marketed drugs? This article tells the story of a class of drugs known as COX-2 selective inhibitors, which first entered the US market in 1998. They were touted as providing safe and effective treatment for various forms of pain and inflammatory illnesses, and the early safety and efficacy profiles looked favorable. Expanded use of these products and postmarket studies generated ever-growing databases of information about the safety and efficacy profiles of COX-2s. Over the years that followed, these data eventually prompted FDA, pharmaceutical companies and Congress to take action, and led to the further evolution of the US drug development landscape. Events Leading up to Withdrawal of Vioxx The backdrop of safety concerns about COX-2 selective inhibitors was established in December 1998, when Searle (now Pfizer), received approval to market a novel COX-2 inhibitor, Celebrex (celecoxib) capsules, indicated for the treatment of signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA). Safety concerns at this time were not based on cardiovascular risk, but were focused instead on gastrointestinal (GI) risk; long-term studies to assess GI risks of Celebrex had not yet been performed. Because of the limited data regarding long-term use of Celebrex, the lowest possible dosing was recommended (200 mg per day) and alternative therapies for high-risk GI patients were suggested.1 Only a few months later, in April 1999, Merck’s Vioxx (rofecoxib) tablets got a unanimous recommendation by the Arthritis Drugs Advisory Committee for approval for the treatment of signs and symptoms of OA and acute pain. The NDA for Vioxx received a six-month priority review by FDA because the drug potentially provided a significant therapeutic advantage over existing approved drugs due to fewer GI side effects, including bleeding. In May 1999, Merck received approval to market Vioxx tablets in the US for the relief of the signs and symptoms of OA, management of acute pain in adults, and treatment of menstrual pain, with three strengths approved: 12.5 mg, 25 mg and 50 mg. The labeling included warnings on GI risks that were almost identical to those on the labeling for Celebrex, and this language was also incorporated in the labeling for all nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). The original safety database for Vioxx included almost 5,000 patients, and the adverse events listed in the original approved labeling did not show an increased risk of heart attack or stroke,2 although a prospective cardiovascular outcome study was not part of the original NDA. A third COX-2 selective inhibitor, Bextra (valdecoxib) tablets from Searle, was approved in November 2001 for the relief of signs and symptoms of OA and adult RA, and for the treatment of primary dysmenorrhea. Once again, the approved labeling included information regarding GI risks associated with NSAIDs, but did not include information regarding concerns about cardiovascular risk associated with either the class of drug or Bextra itself.3 Celebrex, Vioxx and Bextra, all COX-2 selective inhibitors, are differentiated from other NSAIDs (e.g., naproxen, ibuprofen, ketoprofen) by limiting selectivity for the COX-1 inhibitor, which helps to maintain a normal stomach lining. Before the development of COX-2 selective inhibitors, NSAIDs inhibited both enzymes, so while treating pain and inflammation they also increased the risk of ulcers resulting from damage to the stomach lining. Celebrex, Vioxx and Bextra offered the expected benefit of reducing GI risks, but that benefit had not been fully demonstrated in controlled clinical trials at the time these COX-2s were approved. In an effort to explore longer-term GI effects of Vioxx, Merck launched a postapproval study, Vioxx GI Outcomes Research (VIGOR). VIGOR was a large study of 8,000 patients with RA requiring high doses of anti-inflammatory medication. The study compared Vioxx 50 mg once daily to naproxen 500 mg twice daily. There was no placebo arm. The results were submitted Regulatory Focus 19 Table 1. Key Events in the US Regulatory History of COX-2 Antagonists Celebrex 12/31/1998 Celebrex initial approval: OA and RA Vioxx 5/20/1999 Vioxx initial approval: OA, acute pain, primary dysmenorrhea Celebrex 10/18/2001 Celebrex approved for acute pain and primary dysmenorrhea Bextra 11/16/2001 Bextra initial approval: OA, RA, primary dysmenorrhea Vioxx 4/11/2002 Vioxx approved for RA Bextra 11/1/2002 Bextra: Labeling change to include risk of serious skin reaction Vioxx 3/26/2004 Vioxx approved for acute treatment of migraine in adults Vioxx 8/19/2004 Vioxx approved for Pediatric indication (Juvenile RA) Vioxx 9/30/2004 Merck voluntarily withdraws Vioxx worldwide Celebrex Mar-05 FDA issues Alert regarding Celebrex and risk of CV events Bextra 4/7/2005 FDA asks Pfizer to remove Bextra from the market Celebrex 7/29/2005 Celebrex approved for ankylosing spondylitis Celebrex 7/29/2005 Celebrex label changed to include boxed warning (additional CV risks) Celebrex 12/15/2006 Celebrex approved for Pediatric indication (Juvenile RA) Arcoxia Apr-07 Merck receives a Not Approvable letter for Arcoxia Prexige Oct-07 Novartis receives a Not Approvable letter for Prexige to FDA in June 2000. In April 2002, the data from VIGOR and other studies resulted in the approval of Vioxx for RA at a lower dose (25 mg) and a change to the labeling regarding GI risk: the new wording read, “risk of GI toxicity with Vioxx 50 mg once daily is significantly less than with naproxen 500 mg twice daily.”4 This data from the VIGOR study provided an argument for the GI-sparing benefit of Vioxx. Two additional safety flags were raised in FDA’s review of this data, however. Of primary concern was the apparent potential risk for cardiovascular events, which was addressed via changes to the labeling. In addition, chronic use of the 50 mg dose of Vioxx was not recommended. Following the April 2002 approval of the supplemental NDA for the RA indication for Vioxx, FDA added cardiovascular risk monitoring as a requirement for all trials using Vioxx, and required Merck to submit all cardiovascular data from ongoing trials. FDA also began to monitor retrospective epidemiologic studies for increased risk of cardiovascular events with Vioxx. In May 2002, Novartis launched the Therapeutic Arthritis Research & Gastrointestinal Event Trial (TARGET) study of its investigational COX-2 selective inhibitor drug Prexige (lumiracoxib), for the treatment of arthritis symptoms and pain. The primary objective was to examine the GI safety of Prexige compared with ibuprofen and naproxen, and a secondary endpoint included cardiovascular risk, marking one of the first times that cardiovascular risk was identified as an endpoint in a clinical NSAID study. Based on an evaluation of more than 18,000 patients, results were published in August 2004 showing a reduced GI risk for Prexige (0.32%) compared to the NSAID comparators (0.91%). Further, the results did not show that Prexige demonstrated a difference in cardiovascular risk against NSAIDs 20 December 2009 overall.5 Although Prexige was approved for marketing in the UK in 2005 and in the EU in 2006,6 the NDA submitted in 2002 did not result in FDA approval. Based on study findings of liver damage in patients taking Prexige, EMEA’s Committee for Medicinal Products for Human Use recommended withdrawal of the drug in December 2007 and EMEA revoked the marketing authorization in March 2008.7,8 A retrospective study analyzing 6 million Kaiser patients taking COX-2 selective and nonselective NSAIDs that had begun in 2002 (with partial FDA funding) showed a fivefold increased risk of acute myocardial infarction associated with the use of 50 mg/ day of Vioxx compared with 1000 mg/day of Celebrex. The study results were presented by David Graham, MD, of FDA’s Office of Drug Safety at the International Conference on Pharmacoepidemiology & Therapeutic Risk Management meeting in France in August 2004,9 and the results prompted FDA to consider the need for additional warnings on the Vioxx label. During this same time period, Merck completed studies for expanded indications for Vioxx and achieved FDA approval for the treatment of migraine in adults (March 2004) and for juvenile RA (August 2004). Just after Dr. Graham’s presentation, in September 2004, Merck announced the results of its Adenomatous Polyp Prevention On Vioxx (APPROVe) study—to investigate whether Vioxx could prevent the recurrence of colon polyps—which showed an increased risk of thromboembolic events, particularly myocardial infarction, in patients treated for more than 18 months with 25 mg Vioxx twice daily in comparison with placebo-treated patients. This study was halted by its Data Safety Monitoring Board due to the increased risk of cardiovascular events in patients who received Vioxx. After meeting with FDA on 28 September 2004 to discuss this action, Merck publicly announced a voluntary, worldwide withdrawal of Vioxx on 30 September 2004. As a separate and interesting point, in 2004 both Vioxx and Celebrex were widely advertised directly to consumers (DTC). Pfizer voluntarily curtailed its DTC advertising of Celebrex following the Vioxx withdrawal, only recently resuming it in 2007. • • • The Fallout Fallout from the events leading up to the Vioxx withdrawal was widespread and included changes within and by FDA, as well as changes initiated by Congress. Changes at FDA In November 2004, FDA announced its Drug Safety Initiative,10 which included changes to physician and patient information, restructuring at the Center for Drug Evaluation and Research (CDER), an effort to enhance the culture of safety in CDER by creating the Drug Safety Oversight Board,11 enhancements to risk communications efforts, a focus on modernization of the drug development process called the Critical Path Initiative, and the development of data standards and processes to improve sharing of drug safety information. Following discussions at the February 2005 joint meeting of the Arthritis and Drug Safety and Risk Management Advisory Committees, FDA published a summary of the cardiovascular risk associated with the approved COX-2 inhibitor NSAIDs in April 2005: • The approved COX-2 selective drugs are associated with an increased risk of serious adverse cardiovascular events, at least at some doses, with reasonably prolonged use, and currently available data do not allow for a rank ordering of these drugs with regard to cardiovascular risk. • It was not possible to conclude that the COX-2 selective drugs confer an increased risk over nonselective NSAIDs in chronic use. • There are no data from long-term placebo-controlled trials for the nonselective NSAIDs (other than the preliminary data for naproxen) that are analogous to the data available for the COX-2 selective agents.12 The recommendations from this report included: • a black box warning and contraindication labeling for the NSAID class • a Medication Guide for all prescription NSAIDs13 • • a request to sponsors of all nonselective NSAIDs to conduct and submit for FDA review a “comprehensive review and analysis of all available data from controlled clinical trials to further evaluate the potential risk of serious adverse cardiovascular events” no change to the availability of nonprescription NSAIDs the addition of a black box warning for Celebrex regarding cardiovascular risk and a recommended postmarket study commitment to further explore the longterm safety of Celebrex in comparison to its competitors withdrawal of Bextra from the market (cardiovascular risk in this case was compounded by the high rate of reporting of serious skin reactions; the drug was subsequently withdrawn) careful review of any proposal from Merck to resume marketing of Vioxx, including review by FDA’s Drug Safety Oversight Board and an advisory committee Beyond this report, some other events followed at FDA: • The Office of Drug Safety was restructured to report directly to the director of CDER. • A new pilot program was put in place to evaluate the safety status of new molecular entities (NMEs), postmarket. • FDA requested DTC advertising changes. • Lumiracoxib was not approved. As a result of public concern over risks posed by approved drugs, FDA and the Department of Health and Human Services requested the Institute of Medicine (IoM) to conduct a study on drug safety. IoM’s report, “The Future of Drug Safety: Promoting and Protecting the Health of the Public,” released in September 2006, took into consideration the full scale of safety-related activities performed during drug development, including the roles of FDA and other stakeholders that monitor, evaluate, improve and ensure drug safety. A summary of the IoM report is provided in the sidebar. FDA agreed that its responsibility includes balancing expeditious access to drugs with concerns for safety. Three key efforts summarize FDA’s response to the IoM report. • FDA launched initiatives to: develop new scientific approaches to detecting, understanding, predicting and preventing adverse events; develop and incorporate new quantitative tools in the assessment of benefit and risk; and conduct a pilot program to review the safety profiles of certain Regulatory Focus 21 • • newly approved drugs on a regularly scheduled basis. The agency focused on communication and information flow among all stakeholders engaged in promoting the safe use of medical products (e.g., an advisory committee was established to provide input to improve FDA’s risk communication policies and practices, a comprehensive review of public communication tools was performed and a comprehensive risk communication strategic plan was developed). FDA announced its plans to improve operations and management to ensure implementation of the review, analysis, consultation and communications processes needed to strengthen the drug safety system.14 FDA’s Critical Path Initiative and Drug Safety Initiative focus on incorporating cutting-edge science into clinical drug development, using tools to try to predict human safety outcomes and using genomic or other tools to identify those at high risk for side effects and subgroups with a high probability of positive response.15 Congressional Influence As public awareness of the cardiovascular safety concerns regarding Vioxx grew, members of Congress were vocal in expressing their thoughts regarding drug safety and accountability in the drug development and approval process. In response to these concerns and growing pressure to reinforce the oversight of postmarket activities, the Food and Drug Administration Amendments Act of 2007 (FDAAA) was signed into law on 27 September 2007. This legislation has been described by FDA personnel as the most substantial change in drug law since 1938. FDAAA gave FDA new authority to mandate postapproval clinical trials and expedite mandatory safety-related labeling changes, and introduced Risk Evaluation and Mitigation Strategies (REMS) to replace the former RiskMAP program. Impact on Drug Development FDA scrutiny of sponsors’ completion of postmarket studies of approved products is demonstrated by CDER’s publicly available Postmarketing Study Commitments database16 22 December 2009 and the postmarketing commitments guidance document issued in February 2006.17 Annual reports from the database are sent to Congress to show the percentage of completed and outstanding study commitments by sponsors. These reports impact public perception of how seriously sponsors view commitments made during the approval process for postmarket studies, especially safety studies. Emphasis on these studies will no doubt be bolstered further by FDA’s new authority to mandate postapproval clinical trials. Risk management guidances including Guidance for Industry: Development and Use of Risk Minimization Action Plans (March 2005), Guidance for Industry: Premarketing Risk Assessment (March 2005) and Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (March 2005) have been issued. Originally scheduled for release in 2004, FDA’s delivery of these documents was likely impacted by the Vioxx withdrawal. The agency published additional guidance documents on safety topics, e.g., Drug Safety Information—FDA’s Communication to the Public, as mentioned earlier, and a new Manual of Policies and Procedures for the Drug Safety and Oversight Board. New REMS provisions set forth by FDAAA create a consistent set of risk management tools that can be applied to both new and approved drugs. These tools enable FDA to require labeling changes, including the creation of Medication Guides, communication plans, implementation plans and other elements to ensure safe use. By early 2009, implementation of REMS impacted approval timelines, with two- to nine-month delays for products requiring a REMS.18 REMS requirements most frequently called for Medication Guides.19 Approximately a third of all drug and biologic applications approved in the past year included a REMS. In the same time frame, CDER required 46 postmarket safety-related studies and 15 safety-related labeling changes for marketed products.20 Celebrex, continuously on the market since 1998, is now the only COX-2 available in the US (see Table 1). No further COX-2 products have been approved by FDA due to the requirement to demonstrate benefit beyond noninferiority to other marketed products in the class. Dr. John Jenkins, director of CDER’s Office of New Drugs, has acknowledged that the agency often holds “me-too” products to a higher approval standard due to the evolving regulatory landscape accompanying the approval of additional agents in a class.21 Dr. Robert Temple, director of the Office of Medical Policy at CDER, has suggested that sponsors of new NSAIDs conduct a crossover trial, in which patients who do not respond to a marketed product are randomized to either continue taking the marketed product or to receive the new drug.21 The Environment Today Following the February 2005 joint meeting of its Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee, FDA mandated that all new NSAIDs would require large outcome trials of 10,000 to 20,000 OA (and possibly RA) patients. These trials would require a treatment duration of two years for a substantial number of patients and a controlled study design using naproxen and nonnaproxen NSAIDs as active comparators. These data are now required in the initial NDA for approval of an NSAID. FDA’s Medication Guide for NSAIDs lists both cardiovascular and GI effects as potential serious side effects associated with the use of this class of drugs.22 The story of COX-2 inhibitors demonstrates how FDA is able to address serious drug development issues affecting a drug class. Actions taken by Congress to confer additional legal authority upon FDA demonstrate the governmental checks and balances system and federal regulation change process in action. The public nature of the withdrawal of Vioxx and Bextra also raised consumer awareness about the potential risks associated with pharmaceutical products. Perhaps most important, what happened with Vioxx and Bextra highlights the critical balance between the time needed to demonstrate safety with pharmaceuticals prescribed for long-term use and the pressure to make drugs commercially available to patients. Vioxx may have put industry and FDA in a better position to address similar situations in the future. The withdrawal of Vioxx triggered a flurry of congressional hearings, during which FDA’s ability to resolve drug safety problems came under fire. Some members of Congress have repeatedly criticized the agency for failing to disseminate safety concerns about drugs such as Vioxx as soon as initial, though nondefinitive, safety signals were available. According to remarks by former FDA Commissioner Mark McClellan, who left the agency in early 2004, pressure on FDA to hold drugs to a higher standard of safety has increased dramatically since Vioxx.23 FDA staffers reject the bar-raising theory, pointing out that the ratio of drugs approved to applications submitted has held steady in recent years, but FDA approved just 16 NME drug applications in 2007,24 a 20-year low that is 36% below the annual average over The Future of Drug Safety: Promoting and Protecting the Health of the Public (Institute of Medicine Report) The Institute of Medicine report noted the perception of crisis that compromised FDA’s and industry’s credibility following the Vioxx withdrawal. The report agreed on the need for change and noted issues related to resource constraints and an organizational culture at FDA that was not optimally functional, unclear and insufficient enforcement mechanisms and a lack of consistently accountable and transparent processes to communicate safety concerns to the public and healthcare professionals in a timely and effective manner. Recommendations in the report included: • labeling requirements and advertising limits for new medications • clarified authority and additional enforcement tools for the agency • clarification of FDA’s role in gathering and communicating additional information on marketed products’ risks and benefits • mandatory registration of clinical trial results to facilitate public access to drug safety information • increased role for FDA’s drug safety staff • large boost in funding and staffing for the agency (Available at www.iom.edu/ CMS/3793/26341/37329.aspx) the last decade,25 and 21 NME drug applications in 2008,26 many of which were for narrow indications or rare diseases. Many recent approvable and not-approvable decisions from FDA suggest that the number of approvals, particularly firstaction approvals, is unlikely to increase markedly in the near future. Sponsors should continue to prepare complete NDAs based on development plans that capitalize on the lessons from scrutiny of the COX-2 inhibitors. References 1. Celebrex Label, approved 5 January 1999. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/1998/20998lbl.pdf. 2. Vioxx Label, approved 20 May 1999. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/1999/21042lbl.pdf. 3. Bextra Label, approved 16 November 2001. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2001/21341lbl.pdf. 4. Vioxx Label, approved 11 April 2002. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2002/21042s7lbl.pdf. 5. “Novartis Is Confident In Prexige’s Prospects Despite Arcoxia AC Debacle,” The Pink Sheet,30 April 2007. 6. “Novartis to Resubmit Prexige NDA in 2007,” The Pink Sheet, 11 November 2006. Available at www.fdaweb.com/ login.php?sa=v&aid=D5104187&cate=&stid=%241%248 e..vX1.%24DgUD5yAS16wox34RJb.FW. 7. Official Journal of the European Union, c104. Available at http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri =OJ:C:2008:104:0012:0022:EN:PDF. 8. EMEA decision about Prexige. Available at www. emea.europa.eu/pdfs/human/press/pr/QA_ Lumiracoxib_53636307en.pdf. Regulatory Focus 23 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 24 The Pink Sheet, 30 August 2004, page 6. FDA’s Drug Safety Initiative. Available at www.fda.gov/ cder/drugSafety.htm. FDA’s Drug Safety Oversight Board MAPP. Available at www.fda.gov/downloads/AboutFDA/ ReportsManualsForms/StaffPoliciesandProcedures/ ucm073564.pdf. Memorandum by John K. Jenkins and Paul K. Seligman regarding “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk.” Available at www.fda.gov/ ohrms/dockets/ac/06/briefing/2006-4202B1_09_FDATab09.pdf. FDA’s NSAID Medication Guide. Available at www.fda. gov/downloads/Drugs/DrugSafety/UCM088567.pdf. www.fda.gov/bbs/topics/NEWS/2007/NEW01551.html. FDA’s Critical Path Initiative. Available at www.fda.gov/ ScienceResearch/SpecialTopics/CriticalPathInitiative/ ucm076689.htm. FDA’s Postmarketing Study Commitments Database. Available at www.accessdata.fda.gov/scripts/cder/pmc/ index.cfm. FDA, Guidance for Industry: Reports on the Status of Postmarketing Study Commitments— Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997. Available at www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM080569.pdf. “The REMS Effect: Delays From FDA REMS Reviews Becoming Clearer,” The Pink Sheet. 12 January 2009. List of approved REMS. Available at www.fda. gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ucm111350.htm. “New Law Boosts Safety Strategies in New Approvals: Dal Pan,” FDAWebview, 23 April 2009. Available at www.fdaweb.com/login.php?sa=v&aid=D5111483&cate= &stid=%241%24OL4.9c5.%24RwXd2kDu2saL9ZFjkmxwe. December 2009 21. 22. 23. 24. 25. 26. “Negative Arcoxia Review May Reflect Increasingly High Hurdle for Me-Toos,” The Pink Sheet, 23 April 2007. www.hhs.gov/asl/testify/2008/02/t20080227e.html. McClellan M. “Drug Safety Reform at the FDA— Pendulum Swing or Systematic Improvement?” NEJM, 26 April 2007. Available at http://content.nejm.org/cgi/ content/full/NEJMp078057. “NME and NDA Approvals Decline in 2007,” FDAWebview, 7 January 2008. Available at www.fdaweb. com/login.php?sa=v&aid=D5107610&cate=&stid=%241% 24Ld..2Z%2F.%24mT9g3UXpjAzG5cMpnJwED%2F. Scott Gottlieb, MD, deputy commissioner for medical and scientific affairs, Food and Drug Administration, remarks at Seventeenth Annual Cancer Progress Conference, New York, NY; 6 March 2007. Available at www.fda.gov/ NewsEvents/Speeches/ucm052340.htm. FDA Drug Approval Reports. Available at www.fda.gov/ cder/rdmt/default.htm. Acknowledgements The author is grateful to Olivia Pinkett and Anne Stokley of GlaxoSmithKline for their constructive contributions to this manuscript. Author Julia S. Rivers, MA, is a program manager in policy, intelligence and education in US regulatory affairs at GlaxoSmithKline. Originally a music teacher by training, she has worked in the pharmaceutical industry for 18 years, specializing in the development and delivery of regulatory training and awareness sessions and eLearning modules, IT and communications skills training, process improvement, and project management. Rivers holds an MA in international peace and conflict resolution from Arcadia University and currently is completing an MS in quality assurance/regulatory affairs at Temple University.