For other versions of this document, see http://wikileaks.org/wiki/CRS-RL33925 ------------------------------------------------------------------------------ Order Code RL33925 Drug Safety: A Side-by-Side Comparison of Bills in the 110th Congress March 13, 2007 Susan Thaul Specialist in the Regulation of Prescription Drugs and Biologics Domestic Social Policy Division Drug Safety: A Side-by-Side Comparison of Bills in the 110th Congress Summary Members of Congress and the public are increasingly concerned about the ability of the Food and Drug Administration (FDA) to ensure that the drugs sold in the United States are safe and effective. In November 2004, FDA asked the Institute of Medicine (IOM) to assess the current system for evaluating and ensuring drug safety and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs. IOM released The Future of Drug Safety: Promoting and Protecting the Health of the Public in September 2006, and FDA issued its response in January 2007. The following drug safety bills have been introduced in the 110th Congress: S. 468 / H.R. 788, S. 484, and H.R. 1165. Although the legislation and the IOM report address many of the same drug safety issues, the bills differ in their treatment of FDA authority to require action and to enforce compliance, comparative effectiveness studies, and how to fund any additional agency activities. For example, S. 468 / H.R. 788 would strengthen FDA's post-approval drug safety activities by creating a new Center for Postmarket Evaluation and Research for Drugs and Biologics. The other bills would leave these activities where they currently reside in the Center for Drug Evaluation and Research. All the bills would allow the FDA to penalize (through civil fines, injunctions, or withdrawal of marketing approval or licensure) drug manufacturers who did not conduct required postmarket studies or who failed to report study results. The IOM committee recommended that Congress provide substantially increased resources to FDA to bolster its drug safety activities. S. 468 / H.R. 788 would authorize appropriations to carry out the bill's provisions, S. 484 would rely on user fees, expanding FDA's existing authority to use such fees, and H.R. 1165 does not address funding. Contents Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Report Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 FDA organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 FDA authority to require action and to enforce compliance . . . . . . . . . 2 Comparative-effectiveness studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 FDA funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Comparison of Drug Safety Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Organizational culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Science and expertise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 List of Tables Table 1. Comparison of Drug Safety Provisions in S. 468 / H.R. 788, S. 484, and H.R. 1165 in Relation to Recommendations in the Institute of Medicine September 2006 Report and the Food and Drug Administration's January 2007 Response . . . . . . . . . . . . 4 Drug Safety: A Side-by-Side Comparison of Bills in the 110th Congress Background Members of Congress and the public are increasingly concerned about the ability of the Food and Drug Administration (FDA) to ensure that the drugs sold in the United States are safe and effective. Legislators, industry, the public, and FDA scientists have raised questions about FDA's collection and release of safety data, and whether the agency has the authority and resources to ensure adequate research over the marketing life of the pharmaceutical products it regulates. In 2004, the regulatory, medical, and industry debate became very public with reports of cardiovascular hazards posed by the pain medicine Vioxx (one of several COX-2 nonsteroidal antiflammatory drugs then on the market), and of children facing increased risk of suicidal thoughts and actions when taking certain antidepressants (such as the selective serotonin reuptake inhibitors Paxil and Zoloft). Not only was Congress asking whether the manufacturers knew of these risks while continuing to market the drug, but also whether FDA should have known of the risks and done more to protect the public. At the height of public and Congressional attention, FDA asked the Institute of Medicine (IOM) to "conduct an independent assessment of the current system for evaluating and ensuring drug safety postmarketing and make recommendations to improve risk assessment, surveillance, and the safe use of drugs." IOM released its report in September 2006.1 FDA issued its response in January 2007 and noted relevant activities the agency has begun and others it has planned.2 Among the planned activities are those in its proposal for a reauthorization of the prescription drug user fee program (PDUFA IV).3 1 Institute of Medicine (IOM), The Future of Drug Safety: Promoting and Protecting the Health of the Public, Alina Baciu, Kathleen Stratton, Sheila P. Burke, Editors, Committee on the Assessment of the US Drug Safety System, Board on Population Health and Public Health Practice (Washington, DC: National Academies Press, 2006). 2 Food and Drug Administration (FDA), "The Future of Drug Safety -- Promoting and Protecting the Health of the Public: FDA's Response to the Institute of Medicine's 2006 Report," January 2007. 3 Congress first gave FDA authority to collect these fees with the Prescription Drug User Fee Act of 1992; reauthorized twice, the current authority expires Oct. 1, 2007. See CRS Report RL33914, The Prescription Drug User Fee Act (PDUFA): Background and Issues for PDUFA IV Reauthorization, by Susan Thaul. CRS-2 In the meantime, several Members of Congress have introduced bills to address drug safety and FDA's role in protecting the public's health. Report Highlights This report provides a side-by-side comparison of: ! Institute of Medicine: recommendations in its September 2006 report, The Future of Drug Safety: Promoting and Protecting the Health of the Public; ! Food and Drug Administration: announced actions and plans to address problems identified in the IOM report; ! S. 468 / H.R. 788 (the Food and Drug Administration Safety Act of 2007), introduced on January 31, 2007, by Senators Grassley, Dodd, Mikulski, and Bingaman, and Representatives Tierney and Ramstad; ! S. 484 (the Enhancing Drug Safety and Innovation Act of 2007), introduced on February 1, 2007, by Senators Enzi and Kennedy;4 and ! H.R. 1165 (the Swift Approval, Full Evaluation (SAFE) Drug Act), introduced on February 16, 2007, by Representative Markey. The bills and the IOM report address many of the same issues, often with similar approaches though at times with major differences. The IOM report addressed only drugs, not biological products (e.g., vaccines), in keeping with the charge FDA gave it. FDA's response to the IOM recommendations, therefore, relates to drugs, but also states that the approach to drug safety is relevant to all medical products. All the bills would amend the Federal Food, Drug, and Cosmetic Act (regarding the regulation of drugs); S. 484 would also amend the Public Health Service Act (regarding the regulation of biologics). Highlighted below are a few of the more significant items regarding drug safety. FDA organization. S. 468/H.R. 788 would remove the post-approval drug safety activities from FDA's Center for Drug Evaluation and Research (CDER) and create a new Center for Postmarket Evaluation and Research for Drugs and Biologics (the Center). The IOM report does not suggest that approach to strengthen FDA's postmarket activities, nor do the other pending bills. FDA authority to require action and to enforce compliance. The bills and the IOM recommendations aim to strengthen FDA's ability to make sure drug manufacturers (application sponsors) appropriately design and conduct postmarket studies and disclose the results to the public. S. 468/H.R. 788 lays out requirements that the new Center for Postmarket Evaluation and Research for Drugs and Biologics would administer; S. 484 would achieve this with a process it calls a Risk Evaluation and Mitigation Strategy (REMS); and H.R. 1165 would allow the Secretary to require certain studies. The IOM recommended and all the bills would allow the Secretary to penalize (through civil fines, injunctions, or withdrawal of marketing approval or 4 This report covers Title I (Risk Evaluation and Mitigation Strategies) of S. 484; it does not cover Title II (Reagan-Udall Institute for Applied Biomedical Research), Title III (Clinical Trials), or Title IV (Conflicts of Interest). CRS-3 licensure) sponsors who do not conduct required studies or complete them on time, or who fail to report study results. Comparative-effectiveness studies. The IOM report and the bills address the need for FDA authority to require pre- and postmarket studies. S. 468 alone would give FDA the authority to require that those studies compare a drug's safety and effectiveness with that of other drugs. FDA funding. All three bills would require a variety of drug safety activities. They differ in how to fund them. S. 468 / H.R. 788 would authorize appropriations to carry out the bill's provisions; S. 484 would rely on user fees, expanding FDA's existing authority to use such fees; and H.R. 1165 does not address funding. The IOM committee not only recommended that Congress provide "substantially increased resources" to FDA, but noted that all its other recommendations could not be implemented without those resources. Table 1, beginning on page 4, addresses the range of FDA drug safety activities that the IOM recommended, along with FDA's response, and activities that the bills would authorize or require. The table structure follows the 25 IOM recommendations within the five categories of organizational culture, science and expertise, regulation, communication, and resources.5 5 CRS Report RL32797, Drug Safety and Effectiveness: Issues and Action Options After FDA Approval, by Susan Thaul, addresses many of the topics covered in the IOM report and the Senate bills. The IOM report also addressed clinical trial registration and results database requirements; a separate CRS Report RL32832, Clinical Trials Reporting and Publication, by Erin D. Williams, describes and discusses those recommendations. CRS-4 Table 1. Comparison of Drug Safety Provisions in S. 468 / H.R. 788, S. 484, and H.R. 1165 in Relation to Recommendations in the Institute of Medicine September 2006 Report and the Food and Drug Administration's January 2007 Response S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Organizational culture 3.1 The committee recommends that the Not directed to FDA. No provision. No provision. No provision. FFDCA be amended to require that the FDA Commissioner currently appointed by the President with the advice and consent of the Senate also be appointed for a six-year term of office. The Commissioner should be an individual with appropriate expertise to head a science-based agency, demonstrated capacity to lead and inspire, and a proven commitment to public health, scientific integrity, transparency, and communication. The President may remove the Commissioner from office only for reasons of inefficiency, neglect of duty, or malfeasance in office. 3.2 The committee recommends that an Engaging external No new entity. Refers to No new entity. Refers to the No provision. external Management Advisory Board be consultants to help develop required responsibilities of FDA Drug Safety Oversight appointed by the Secretary of HHS [the comprehensive strategy. the FDA Drug Safety and Board. [Note: FDA limits Department of Health and Human Services] Risk Management Advisory membership to federal to advise the FDA Commissioner in Committee, which it would employees although allowing shepherding CDER [the FDA Center for Drug transfer to the new Center for members from outside of Evaluation and Research] (and the agency as Postmarket Evaluation and FDA.] a whole) to implement and sustain the Research for Drugs and changes necessary to transform the center's Biologics. culture -- by improving morale and retention of professional staff, strengthening transparency, restoring credibility, and creating a culture of safety based upon a lifecycle approach to risk-benefit. CRS-5 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 3.3 The committee recommends that the [See response to No comparable provision; No provision. No provision. Secretary of HHS direct the FDA recommendation 3.2.] however, a related provision Commissioner and Director of CDER, with would establish a Center for the assistance of the Management Advisory Postmarket Evaluation and Board, to develop a comprehensive strategy Research for Drugs and for sustained cultural change that positions Biologics (the new Center) the agency to fulfill its mission, including as a separate entity within protecting the health of the public. FDA (not an administrative office of the FDA Center for Drug Evaluation and Research (CDER) or the FDA Center for Biologics Evaluation and Research (CBER). Would also transfer the Office of Surveillance and Epidemiology (OSE, formerly called the Office of Drug Safety) from CDER to the new Center. 3.4 The committee recommends that CDER Initiated two pilot projects to Would require the new No provision. No provision. appoint an OSE [Office of Surveillance and evaluate models for Center Director to review all Epidemiology] staff member to each New involving OSE staff (1) in applications and supplements Drug Application review team and assign reviews and (2) more and associated analyses joint authority to OND [CDER's Office of significantly, in postmarket before approval. Authorizes New Drugs] and OSE for postapproval decision making. the new Center to require regulatory actions related to safety. postmarket studies Would also improve concerning safety and communication between effectiveness, including OSE and OND and work to comparisons with other assess the impact and value products, specifying date of routinely including due; studies could use postmarket review staff on epidemiology or other premarket review teams. observational designs, or databases. CRS-6 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Established an associate director of safety and a safety regulatory program manager in each CDER OND review division; began regular safety meetings between OSE and all OND review divisions. FDA's proposal for a reauthorized Prescription Drug User Fee Act (PDUFA), which it refers to as PDUFA IV, includes provisions to improve communication and coordination between OSE and OND, including an assessment of the value of including postmarket review staff on premarket review teams. Created new procedures around decision-making about requesting further studies and labeling changes. Creating a standard operating procedure for presenting postmarket safety issues to advisory committees. CRS-7 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 3.5 To restore appropriate balance between PDUFA IV proposal No comparable provision; Would extend the definition No provision. the FDA's dual goals of speeding access to includes safety-related however, the bill would of the activities on which innovative drugs and ensuring drug safety activities, including work authorize appropriations for drug user fees may be used over the product's lifecycle, the committee toward identifying and safety activities [see below]. to include the review and recommends that Congress should introduce assessing risk management implementation of the Risk specific safety-related performance goals in and communication tools; Evaluation and Mitigation the Prescription Drug User Fee Act IV in exploration of benefits of Strategy (REMS [see 2007. adverse event reporting; below]) and the review of acquisition and use of safety information including databases; develop guidance adverse event reports. on pharmacoepidemiologic studies and on clinical hepatoxicity and enriched trial designs; and improve communication between OSE and OND. Science and expertise 4.1 The committee recommends that in Began upgrading the Web- Would not require systematic No provision. No provision. order to improve the generation of new safety accessible Adverse Events and scientific review, but signals and hypotheses, CDER (a) conduct a Reporting System (AERS) II would require that the new systematic, scientific review of the AERS to add signal detection and Center Director improve [FDA's Adverse Event Reporting System] tracking tools. Implementing postmarket surveillance system, (b) identify and implement changes electronic system across programs and activities. in key factors that could lead to a more CDER offices to track efficient system, and (c) systematically postmarket safety issues. implement statistical-surveillance methods on a regular and routine basis for the If PDUFA IV proposal is automated generation of new safety signals. accepted, would seek outside research organizations to study how to maximize public health benefits of the collection and reporting of adverse events over a product's lifecycle. CRS-8 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 4.2 The committee recommends that in Would use PDUFA IV funds Would require that the new No provision. No provision. order to facilitate the formulation and testing to acquire databases and hire Center Director conduct of drug safety hypotheses, CDER (a) increase staff to use them; conduct postmarketing surveillance, their intramural and extramural programs that targeted postmarketing using risk-benefit analyses, access and study data from large surveillance, study drug- adverse event reports, and automated healthcare databases, and (b) class effects, and detect clinical and observational include in these programs studies on drug signals. studies. Would require the utilization patterns and background new Center to contract with incidence rates for adverse events of interest, Sponsoring public meeting domestic and international and (c) develop and implement active to explore opportunities for patient databases (or require surveillance of specific drugs and diseases as linking private- and public- the drug sponsor to do so) to needed in a variety of settings. sector "postmarketing safety conduct epidemiologic and monitoring systems to create other observational studies. a virtual integrated, interoperable Nationwide medical product safety network." Would use PDUFA IV funds to develop guidance on conducting pharmacoepidemiologic studies using large healthcare data sets; would hold public workshop to identify best practices and issue guidance on such practices. Would develop guidance on clinical hepatoxicity and enriched trial designs to support the prevention of safety problems during drug development. CRS-9 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Current data-sharing activities include agreements with the Agency for Healthcare Research and Quality and the Veterans Health Administration, and active monitoring and analysis of influenza vaccine safety. Developing (through the critical path initiatives) techniques for predictive toxicology, identifying drugs' cardiovascular risk, preventing drug-induced liver injury, using integrated information, using new tools to enhance blood safety, and enhancing the safety of gene therapy. 4.3 The committee recommends that the Signed agreement with the No provision. No provision. No provision. Secretary of HHS, working with the Veterans Health Secretaries of Veterans Affairs and Defense, Administration to share develop a public-private partnership with information and expertise drug sponsors, public and private insurers, regarding medical product for-profit and not-for-profit health care safety, effectiveness, and provider organizations, consumer groups, and patterns of use. large pharmaceutical companies to prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health importance. Congress should capitalize the public share of this partnership. CRS-10 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 4.4 The committee recommends that CDER PDUFA IV proposal Would set procedure to Would require a sponsor to No provision. assure the performance of timely and includes work toward require risk management submit a proposed Risk scientifically valid evaluations (whether identifying risk management activities when deemed Evaluation and Mitigation done internally or by industry sponsors) of tools; assessment of selected necessary and would require Strategy (REMS) as part of Risk Minimization Action Plans (RiskMAPs). Risk Minimization Action action to ensure follow-up its application for drug Plans, risk management and and completion of sponsor approval or biologics risk communication tools; requirements. licensure. REMS must annual systematic review and include labeling, reports of public discussion of selected studies and surveillance data, programs and tools and and a pharmacovigilance dissemination of reports; and statement. Based on the public workshops to get estimated number of people prioritization guidance from who would take the drug, industry and others. disease seriousness, expected duration of treatment, and availability of other treatments, the pharmacovigilance statement would provide an assessment of adequacy of REMS activities to assess serious risks, to identify unexpected serious risks of the drug and whether studies are necessary, and, if studies are necessary, to describe what observational and clinical studies are required. CRS-11 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad If the Secretary were to determine it necessary, the Secretary could require that the REMS include a sponsor- developed Medication Guide or patient package insert; a plan to communicate with health care providers, encouraging implementation of relevant REMS components; post-approval observational studies (that the applicant or the Secretary could conduct) or clinical trials, with target schedules for completion and reporting; and restrictions on advertising. Would require an assessment of an approved REMS annually for the first three years after initial approval/licensure and then at a frequency (including none) as specified in the REMS. CRS-12 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 4.5 The committee recommends that CDER Held workshop on Would require that the new Would require REMS to No provision. develop and continually improve a systematic quantitative benefit-risk Center conduct and use risk- include consideration of approach to risk-benefit analysis for use assessment; exploring use of benefit analysis, but would scope of use, seriousness of throughout the FDA in the preapproval and best practices and not require that FDA develop the disease or condition that post-approval settings. identification and testing of and improve a systematic the drug is used to treat or quantitative tools; have approach. prevent, seriousness of introduced training courses adverse events, and other for medical reviewers. available treatment. Created group of internal When concerned about a experts to develop serious risk that may be quantitative methods for related to the pharmacologic safety evaluation, develop class of a drug, the Secretary and disseminate best could defer a REMS practices of safety reviews assessment while convening during product development, meetings of the public, and to provide consistency advisory committees, or across review divisions. expert panels to discuss possible responses to that Initiated critical path concern. initiatives [See response to recommendation 4.2 above] Secretary may coordinate and a pilot program to timetable to review efforts of systematically review safety international marketing profiles of new molecular authorities. entities (NMEs) [See 5.4 below]. Established program with the National Toxicology Program of the National Institute of Environmental Health Sciences to develop animal model to assess cancer risk associated with gene therapy. CRS-13 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Initiative underway to strengthen the safety evaluation process, including standardized methodologies, training and mentoring, workload prioritization, and management tools. 4.6 The committee recommends that CDER [See responses to No provision. No provision. No provision. build internal epidemiologic and recommendations 3.5 and informatics capacity in order to improve the 4.2 above.] postmarket assessment of drugs. 4.7 The committee recommends that the Commissioner of FDA demonstrate commitment to building the agency's scientific research capacity by: a) Appointing a Chief Scientist in the office Commissioner proposed No comparable provision, No provision. No provision. of the Commissioner with responsibility for creation of the Office of the but the bill would create a overseeing, coordinating, and ensuring the Chief Medical Officer to separate Center for quality and regulatory focus of the agency's oversee FDA scientific Postmarket Evaluation and intramural research programs. operations. Research for Drugs and Biologics (the new Center) and the position of Director of the new Center. b) Designating the FDA's Science Board as Asked the FDA Science No provision. No provision. No provision. the extramural advisory committee to the Board to review scientific Chief Scientist. needs and activities across FDA; engaging external consultants to help develop comprehensive strategy to improve organizational culture. c) Including research capacity in the Not addressed. No provision. No provision. No provision. agency's mission statement. CRS-14 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad d) Applying resources to support intramural Not addressed. Would require that the new No provision. No provision. research approved by the Chief Scientist. Center conduct postmarket risk assessments. e) Ensuring that adequate funding to support Not addressed. Would authorize Would allow for user-fee No provision. the intramural research program is requested appropriations [see below]. revenue to be used for in the agency's annual budget request to REMS evaluation activities. Congress. 4.8 The committee recommends that FDA Conducting pilot program to No comparable provision, Secretary may convene an No provision. have its advisory committees review all review new molecular but the bill would require advisory committee meeting NMEs [new molecular entities] either prior entities [See response to preapproval review by the to review safety concerns or to approval or soon after approval to advise recommendation 5.4 below]. new Center, and would a REMS for a drug or a class in the process of ensuring drug safety and require advisory committee of drugs. efficacy or managing drug risks. consultation before the new Center Director makes a safety determination or orders a corrective action. 4.9 The committee recommends that all Will increase (to the extent No provision. No provision. Would require HHS FDA drug product advisory committees, and feasible) Secretary to allow FDA staff any other peer review effort such as pharmacoepidemiology to present information to an mentioned above for CDER-reviewed product experts support to advisory advisory committee if staff is safety, include a pharmacoepidemiologist or committees. working on a topic the an individual with comparable public health committee is considering. expertise in studying the safety of medical products. 4.10 The committee recommends FDA Will issue new guidances to No provision. No provision in Title I; No provision. establish a requirement that a substantial address the granting and related provisions are in Title majority of the members of each advisory disclosure of conflict-of- IV ("Conflicts of Interest"). committee be free of significant financial interest waivers for advisory involvement with companies whose interests committee members, and to may be affected by the committee's improve the release of deliberations. advisory committee briefing materials to the public. Will make advisory committee member recruitment more transparent by issuing lists of vacancies. CRS-15 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 4.11 To ensure that trial registration is Not directed to FDA. [Note: Senators Dodd and Grassley introduced a separate bill No provision. mandatory, systematic, standardized, and (S. 467) that addresses the issues of clinical trial registration complete, and that the registration site is able and results databases. The comparison of that bill to Title III to accommodate the reporting of trial results, of S. 484 and the IOM report recommendations appears in a the committee recommends that Congress separate CRS product: CRS Report RL32832, Clinical Trials require industry sponsors to register in a Reporting and Publication, by Erin D. Williams.] timely manner at clinicaltrials.gov, at a minimum, all Phase 2 through 4 clinical trials, wherever they may have been conducted, if data from the trials are intended to be submitted to the FDA as part of an NDA [new drug application], sNDA [supplemental new drug application], or to fulfill a postmarket commitment. The committee further recommends that this requirement include the posting of a structured field summary of the efficacy and safety results of the studies. 4.12 The committee recommends that FDA Not accepted. Would require that FDA post Would require that FDA post Would require, within 24 post all NDA review packages on the all studies required under the all approved professional hours of approval, that the agency's website. preapproval and labeling and any required Secretary publish a summary postapproval requirements of patient labeling in a statement of the scientific this section. searchable electronic basis for the approval and repository. how the decision balanced risks and benefits. The statement must include a description of controversies and differences of opinion within FDA and their resolutions, and include any statement submitted for the summary by involved staff. CRS-16 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 4.13 The committee recommends that CBER Decisions to publicly Would require that FDA Would require that the drug Would require biennial review teams regularly and systematically disclose assessments of publish in the Federal sponsor submit REMS reports on approved analyze all postmarket study results and postmarketing safety studies Register and post on the assessments at least annually applications supported by make public their assessment of the must be made on a case-by- Internet drug safety and for the three years after noninferiority studies, and significance of the results with regard to the case basis. effectiveness information. approval/licensure; after that biannual reports regarding integration of risk and benefit information. at increased or reduced postmarket studies. Will publish newsletter on (including none) frequency FDA website, summarizing as the Secretary determines Would prohibit directing results and methods of to be necessary. Would set FDA staff to distort or postmarket reviews, and time limits for the Secretary suppress scientific research, providing information on to act on initial REMS and analysis, opinion, or emerging safety issues and modification requests. recommendations or to on recently approved wilfully disclose scientific products. A dispute resolution process information that is false, would include timeframes, misleading, or incomplete. Will issue final guidance on and involve review by and Would provide for communicating important recommendations of the disciplinary actions and drug safety information to Drug Safety Oversight Board would require annual healthcare professionals, (with added expertise, if Inspector General reports. patients, and other necessary, from the FDA Would also provide consumers. offices of Pediatrics, whistleblower protection Women's Health, and Rare (with provisions for Diseases). enforcement and penalities) and the right to publish. CRS-17 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Regulation 5.1 The committee recommends that Not directed to FDA. Would authorize FDA to Would require that the drug Would authorize the Congress ensure that the Food and Drug require safety and sponsor submit a REMS for Secretary, after providing Administration has the ability to require effectiveness studies, each new drug and biologic, public notice, to order the such postmarketing risk assessment and including in comparison to for a generic drug (all sponsor to conduct studies to risk management programs as are needed other drugs/biologics, information except address safety or to monitor and ensure safe use of drug according to FDA-specified postapproval clinical trials), effectiveness issues products. These conditions may be imposed timetable and terms, if, at for a new indication (either identified after both before and after approval of a new any time, the new Center for a drug with a current approval/licensure. molecular entity, new indication, or new Director determines the REMS or a drug without a dosage, as well as after identification of new need. REMS when a prescription is contraindications or patterns of adverse required for its dispensing), events. The limitations imposed should match Would authorize FDA to and for new safety the specific safety concerns and benefits require limitations on the information. Would allow a presented by the drug product. The risk distribution of a drug or sponsor to submit a REMS assessment and risk management program biologic. These include: assessment at any time. may include: Would authorize the Secretary to require a REMS assessment at any time the Secretary determines that new safety information requires review. Would require that Would allow the following restrictions be commensurate restrictions on distribution or with the risks; necessary; and use during study if Secretary not unduly burdensome on determines it necessary to patient access to drugs. ensure safety and Would authorize FDA to effectiveness (Secretary may require limitations on a order the restrictions product's distribution. These continued, terminated, or include: changed based on study results): CRS-18 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad a) Distribution conditioned on compliance changes in labeling; changes in labeling; with agency-initiated changes in drug labels. b) Distribution conditioned on specific statements in advertisements; disclosure in advertisements warnings to be incorporated into all that the available information promotional materials (including broadcast may not allow for full DTC [direct-to-consumer] advertising). assessment of serious risks; or, if the Secretary determines it necessary, statement in advertisements regarding risk or use information included in the label. c) Distribution conditioned on a moratorium FDA (the new Center) FDA review of restrictions on DTC on direct to consumer advertising. review of advertisements advertisements before they advertising; before they are released; are released; d) Distribution restricted to certain patient or physician training, experience, or certain facilities or physician facilities, pharmacists, or physicians with education; certification of healthcare training or experience; special training or experience. providers, pharmacists, and care setting, or use only in certain settings; a compliance system with restrictions on providers, pharmacists, patients, and others who fail to meet requirements; e) Distribution conditioned on the documentation of safe-use performance of specified performance of specified medical conditions, such as medical procedures; procedures [e.g., requiring a pregnancy test laboratory test results; if a drug might cause abnormal fetal development]. CRS-19 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad f) Distribution conditioned on the the establishment of a risk a new post-approval study or performance of specified additional clinical management plan; changes in the design of an trials or other studies. ongoing study, that FDA could request at the time of approval/licensure or any time afterward; g) Distribution conditioned on the a patient registry; a patient registry or patient maintenance of an active adverse event monitoring; surveillance system. patients to sign a consent form; modification of indication; modification of indication. the monitoring of sales and usage. For a drug approved pursuant to accelerated approval: would require, as a condition of approval, that the sponsor submit and the Secretary approve protocols for postmarket studies, including timeframe and milestones. Until the study commitments are completed, Secretary must require restrictions on distribution and use; CRS-20 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad would also require a statement on labeling that the drug received accelerated approval and that required studies are underway; to include a list of issues being addressed; and labeling to state that FDA gave conditional approval under its accelerated approval process; and that the drug will not receive full approval until completion of studies; would require that the Secretary amend 21CFR314 to require a public meeting if postmarket studies after accelerated approval are not completed within two years; and would require, for a drug approved based on animal efficacy data, studies when ethical and feasible to verify and describe clincial benefit, safety and effectiveness. If a completed study is inconclusive (or not completed within five years), the Secretary would withdraw product from commercial distribution, limiting its availability and requiring informed consent. CRS-21 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 5.2 The committee recommends that Not directed to FDA. If a sponsor were to fail to Would authorize civil money Would consider a drug Congress provide oversight and enact any complete required studies or penalties of $15,000 -- misbranded if it failed to needed legislation to ensure compliance by comply with ordered $250,000 per violation (not comply with postmarket both the FDA and drug sponsors with the corrective action, would to exceed $1 million within study or distribution provisions listed above. FDA needs increased authorize FDA to require one adjudicated proceeding) requirements, or label enforcement authority and better civil monetary fines of for failure to comply with an change orders. enforcement tools directed at drug sponsors, $250,000 for the first 30-day approved REMS. which should include fines, injunctions, and period, doubling for every Would authorize civil withdrawal of drug approval. subsequent 30-day period Would consider a drug penalties of not more than (not to exceed $2 million for misbranded if it failed to 100% (300% if violation any 30-day period); changed comply with the Secretary's caused a consumer harm) of promotion; and withdrawal requirements to change sponsor's gross profits from of product approval or labeling or regarding sales of the drug, or $1 licensure. advertising. million ($3 million if consumer harmed), If the new Center Director [Note: Authority for whichever is greater. determined that a product approval/licensure may present an unreasonable withdrawal already exists in Would authorize the same risk that cannot be law.] penalities for failure to act satisfactorily alleviated by a with "due diligence" to corrective action or if a complete postmarket studies drug's sponsor fails to required based on comply with an order or applications for a fast track requirement, the new Center product or accelerated Director, after consultation approval of a new drug for a with the Director of CBER serious or life-threatening or CBER, could withdraw or illness. suspend the product's approval/licensure. Would also consider a drug to be misbranded if a manufacturer failed to comply with the Secretary's order to make specific label changes to ensure safe and effective use of the drug. CRS-22 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad The Secretary would have to publish in the Federal Register and post on the Internet details regarding reason, factual basis, and reference to supporting empirical data, for determination; explanation that describes why contrary data are insufficient; and position taken by each individual consulted. 5.3 The committee recommends that Not directed to FDA. Does not specify special Does not specify special For drugs approved under Congress amend the FFDCA to require that symbol. symbol, but allows FDA to accelerated approval product labels carry a special symbol such require statement in ads. procedures, would require a as the black triangle used in the UK or an Would authorize FDA, for [Note: As of January 2006, statement on labeling that the equivalent symbol for new drugs, new two years after initial FDA requires date of drug received accelerated combinations of active substances, and new approval/licensure and for all approval but not a symbol on approval and that required systems of delivery of existing drugs. The drugs with outstanding label.] studies are underway, and to FDA should restrict direct-to-consumer required studies, to require include a list of issues being advertising during the period of time the preapproval submission of May require submission of addressed. Would also special symbol is in effect. promotional material, and to advertisements to FDA for require labeling to state that require a statement that the preclearance; specific FDA gave conditional product is new. disclosures in approval under its advertisements, which may accelerated approval process; include approval date, and that the drug will not statement that "existing receive full approval until information may not have completion of studies. identified or fully assessed all serious risks of using the drug," serious adverse events listed in drug's labeling, or "protocol to ensure safe use described in the labeling of the drug...." CRS-23 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad May require temporary moratorium on direct-to- consumer advertisements for up to two years after initial approval if Secretary determines other required disclosure is inadequate to protect public health and safety, and that such prohibition is necessary while additional information is collected, considering expected scope of use, alternatives, and the extent to which studies used to approve the drug may not have identified serious risks. 5.4 The committee recommends that FDA Conducting pilot developed No provision. No provision. No provision. evaluate all new data on new molecular by OSE and OND to review entities no later than five years after systematically the safety approval. Sponsors will submit a report of profiles of new molecular accumulated data relevant to drug safety and entities on a regularly efficacy, including any additional data scheduled basis to determine published in a peer reviewed journal, and will whether these reviews should report on the status of any applicable be initiated for all NMEs. conditions imposed on the distribution of the Will incorporate AERS data, drug called for at or after the time of data mining analysis, approval. epidemiologic data, postmarketing clinical trial information, and a review of the Periodic Safety Update Reports (U.S. Periodic Reports) to identify potential safety concerns early in the product life cycle. CRS-24 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Communication 6.1 The committee recommends that Establishing a new advisory No provision. No provision. No provision. Congress enact legislation establishing a new committee regarding FDA's FDA advisory committee on communication policies and communication with patients and practices; members will consumers. The committee would be include patients and composed of members who represent consumers and experts in consumer and patient perspectives and risk and crisis organizations. The advisory committee would communication and social advise CBER and other FDA centers on and cognitive sciences. communication issues related to efficacy, safety, and use during the lifecycle of drugs and other medical products, and it would support the centers in their mission to "help the public get the accurate, science-based information they need to use medicines and foods to improve their health." CRS-25 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad 6.2 The committee recommends that the Established a working group Would require that FDA Would authorize FDA to No provision. new Office of Drug Safety Policy and to develop a CBER risk make safety issues public via require a MedGuide or Communication should develop a cohesive communication strategic the Federal Register and patient package insert, and a risk communication plan that includes, at a plan. Doing so will explore Internet, but does not require communication plan to minimum, a review of all Center risk communication tools, and development of a plan. providers. communication activities, evaluation and evaluate and improve the revision of communication tools for clarity CBER website. Would require that, not less Would require that the and consistency, and priority-setting to ensure than every 90 days, the Secretary, within one year, efficient use of resources. Established the Secretary publish in the submit to congress an Bioinformatics Board in the Federal Register: assessment of the Office of the Commissioner information about required information technology (IT) to improve the public's studies to include type, infrastructure (data ability to communicate with nature, outcomes, date collection and data mining FDA, including adverse required by FDA or agreed systems, and external event reports and consumer to by sponsor, date for database and personnel complaints. completion, and reason that assets and training programs) any study was not completed that FDA would need to: by deadline; progress reports conduct the activities that and results of completed this bill would require; studies; and explanations of achieve interoperability the new Center Director's among FDA Centers and determinations, if any. product sponsors; and use electronic health records. Also required would be an assessment of whether those assets were sufficient, a plan for enhancing FDA's IT assets, and an assessment of what additional resources FDA would need to make those IT enhancements. CRS-26 S. 468, Grassley-Dodd- Institute of Medicine FDA January 2007 Mikulski-Bingaman & S. 484, Enzi-Kennedy H.R. 1165, Markey September 2006 report recommendations response to IOM report H.R. 788, Tierney-Ramstad Would require the HHS Would require that the Secretary, in consultation Secretary, through FDA and with the FDA Commissioner the National Institutes of and the Directors of the new Health, establish a publicly Center and CDRH, to submit available, searchable a report to Congress about repository of structured, current postmarket electronic product surveillance of FDA- information; and report approved medical devices progress annually to that identifies gaps, Congress. recommends ways to improve them, and identifies changes in authority needed to make those improvements, recognizing the legitimate differences between devices and other medical products. Resources 7.1 To support improvements in drug Notes that PDUFA IV funds, Would authorize Would authorize the use of No provision. safety and efficacy activities over a which require congressional appropriations (beginning PDUFA fees for safety product's lifecycle, the committee action, would not be with $50 million in FY2008, activities specified in this recommends that the Administration should sufficient to fully implement going to $150 million in bill; would amend the request and Congress should approve the IOM recommendations. FY2012) to carry out this PDUFA provisions [21 USC substantially increased resources in both bill's provisions. 379(c)(2)] to include funds and personnel for the FDA. directions for the Secretary's calculation of workload adjustments for annual adjustments to fees. ------------------------------------------------------------------------------ For other versions of this document, see http://wikileaks.org/wiki/CRS-RL33925