Moving Target: Changes at FDA During the Course of the Study1
DRUG SAFETY INITIATIVES
Many of the recent changes stem from the 2004 Food and Drug Administration (FDA) Drug Safety Initiative. The purpose of the initiative is to create a culture of openness and to enhance oversight in FDA. To achieve that FDA has established the Drug Safety Oversight Board (DSB), proposed a Drug Watch Web page, and is soliciting public input on how to expand and establish communication channels with the public to increase transparency (FDA, 2005d).
DRUG SAFETY OVERSIGHT BOARD
The DSB was established in February 2005 (FDA, 2005d) to help FDA realize its vision of culture of openness, enhanced oversight, and transparency in decision making. The DSB is charged with identifying, tracking, and overseeing the management of important drug safety issues in the Center for Drug Evaluation and Research (CDER) (CDER, 2005). A separate board task is to facilitate timely external communication of drug safety issues. Board members—all appointed by the FDA commissioner—include FDA staff, medical experts in other Department of Health and Human Services agencies, and other government departments, and medical experts and representatives of patient and consumer groups. The DSB has 31 members. It
met nine times from its inception through June 2006, and it has generally discussed Patient Information Sheets, Public Health Advisories distributed by CDER, and ways to strengthen CDER’s risk communication efforts.
A Drug Watch Web page was proposed as part of FDA’s drug safety initiative in February 2005 to improve communication with the public on drug safety issues by putting information out as quickly as possible in an easily accessible format. The goal of the proposed Drug Watch program is to help patients and health care professionals make informed decisions on the use of prescription drugs. Drug Watch will include emerging data and risk information in a consumer-friendly form (information sheets) for healthcare professionals and patients regarding drugs for which FDA is actively assessing incoming safety information (FDA, 2005b,d).
A draft guidance on Drug Watch released in May 2005 (FDA, 2005f) discussed how the inclusion of a drug on Drug Watch would not signify that the drug is dangerous or should not be used; it only means that FDA is investigating emerging safety signals. The information on each drug would vary but could include “factual information about newly observed, serious adverse events associated with the use of a drug that have been reported to FDA”; “information about significant emerging risks that FDA believes may be associated with a drug, but that might be avoided by appropriate patient selection, monitoring, or use of concomitant therapy”; and notice of an important risk minimization procedure that has been put into place by the sponsor to alert healthcare providers and patients that there has been a change in how a drug should be prescribed, dispensed, or used (FDA, 2005f). The DSB role in overseeing the Drug Watch program was described above.
STRUCTURAL CHANGES AND LEADERSHIP CHANGES IN THE CENTER FOR DRUG EVALUATION AND RESEARCH
In September 2004, CDER announced that it would be restructuring the Office of New Drugs (OND) and has implemented this in phases throughout 2005–2006 (FDA and CDER, 2005). Phase I of the reorganization involved the elimination of the Office of Drug Evaluation V (ODE V), which began in May 2005 and is now complete. Phase II began in July 2005 with the operation of the new Office of Oncology Drug Products. It also involved the split of the Division of Neuropharmacological Drug Products in ODE I into two new divisions: Neurology and Psychiatry. Phase III began in September 2005 with reassignment of staff in the Division of Therapeutic Biological Internal Medicine Products and the Division of Review Management Policy
in ODE VI to other ODEs and divisions in OND, so that ODE VI could be eliminated (FDA and CDER, 2005).
In October 2005, in his “State of CDER” address to center employees, Steven Galson outlined a proposed center reorganization to “better align staff functions with CDER’s goals and FDA’s public health mission” (FDA, 2005j). According to Dr. Galson, the three goals of the reorganization are to position CDER to be able to participate fully in the Critical Path Initiative (CPI), to increase visibility and a cross-center approach to drug safety, and to centralize risk communication efforts (FDA, 2006a).
As of May 15, 2006, the changes that Dr. Galson outlined in 2005 were put into effect (FDA and CDER, 2005). The reorganization resulted in the lifting of the status (to be at the same level as OND) of the Office of Drug Safety (ODS) whose name was changed to Office of Surveillance and Epidemiology (OSE) and which now reports to the office of the center director. That was done in part to address the perception that drug safety is solely the responsibility of ODS. A new office that reports to the center director and serves as a catalyst for CPI activities was created, with clinical pharmacology and the office of biostatistics reporting to that office. Another change was elevating the Office of Policy and Communication to the office of the center director.
LEADERSHIP CHANGES IN THE FOOD AND DRUG ADMINISTRATION
Over the course of this study, several changes in leadership have taken place in FDA. When the study began, Lester M. Crawford was the acting commissioner; he was confirmed in July 2005 (FDA, 2005i). Soon after his permanent appointment, Dr. Crawford made several changes in FDA leadership, including appointing a new deputy commissioner for medical and scientific affairs, deputy commissioner for operations and chief operating officer, deputy commissioner for international and special programs, and associate commissioner for legislation (FDA, 2005h).
In September 2005, Dr. Crawford abruptly resigned as FDA commissioner (two months after confirmation). Shortly thereafter, President Bush appointed Andrew C. von Eschenbach as the new acting commissioner, and he is still serving in this capacity. In March 2006, President Bush nominated Dr. von Eschenbach to be the permanent head of the agency; as of June 2006, confirmation hearings have not yet taken place.
In June 2005, FDA announced its search for a new director of drug safety in CDER (FDA, 2005g). In late July 2005, the agency announced that CDER Acting Director Steven Galson would be director. In September 2005, FDA announced that it had selected Douglas Throckmorton as the deputy director of CDER. In October 2005, Gerald Dal Pan was named director
of ODS. In April 2006, FDA announced the appointment of Paul Seligman as the CDER associate director for safety policy and communication; this was a newly created position to provide oversight of drug safety issues and policies in CDER (FDA, 2006c).
During the study process, the committee referred to newly released FDA and CDER guidance documents and reports. FDA made additional important changes and undertook reviews of some of its programs. Those are described below.
RECENT MATERIALS FROM THE FOOD AND DRUG ADMINISTRATION
In March 2005, FDA released three final guidance documents to help develop new ways to improve methods of assessing and monitoring risks associated with drugs in clinical development:
Guidance for Industry: Premarketing Risk Assessment (FDA et al., 2005). This guidance focuses on what pharmaceutical companies should consider throughout the clinical trial process to improve the assessment and reporting of safety, to assess important safety issues during trial registration and best practices for the use of data from preapproval safety evaluations, and to build on FDA and International Conference on Harmonisation guidances related to preapproval safety assessments.
Guidance for Industry: Development and Use of Risk Minimization Action Plans (FDA, 2005a). This guidance outlines steps that pharmaceutical companies can take to address goals and objectives related to risk and suggests tools to minimize known risks posed by drugs. These include the consistent use and definition of terms; a framework for ensuring that benefits exceed risks; obtaining input from the public, patients, and health care professionals when deciding to initiate, revise, or end risk minimization plans; and making certain that risk minimization efforts are successful by evaluating risk minimization action plans.
Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (FDA, 2005e). This guidance discusses how to increase postmarketing vigilance to identify safety signals, investigation of the signals, interpreting the signals in terms of risk, and using pharmacovigilance plans to speed the acquisition of safety information with unusual safety signals.
Those guidance documents were issued as part of FDA’s effort to minimize risks while preserving the benefits of medical products. FDA stated that the guidance documents are part of the drug safety initiative announced in 2004 (FDA, 2005d) to improve drug safety and the commitment to transparency (FDA News, 2005a).
FDA released a final guidance in January 2006 titled “Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies” (CDER, 2006). It was one FDA step to “advance the earliest phases of clinical research in the development of innovative medical treatments” (FDA News, 2006a). The guidance discusses specific steps to be taken when exploratory clinical studies on humans are done under an investigational new drug to make the process more efficient and safe.
In November 2005, FDA announced the availability of a white paper titled Prescription Drug User Fee Act (PDUFA): Adding Resources and Improving Performance in FDA Review of New Drug Applications (FDA, 2005c). It was released shortly after FDA requested public input on PDUFA provisions for FDA to consider during the renewal process for 2007 (FDA, 2005k). The white paper describes PDUFA goals, how they were implemented or achieved by CDER, and the changes that have resulted from PDUFA (that is, hiring of more medical reviewers, shorter approval times, greater consistency, and increased workload) (FDA, 2005c).
In February 2006, a report commissioned by FDA, Evaluation of FDA’s First Cycle Review Performance—Retrospective Analysis was released2 (FDA News, 2006c). It showed a positive correlation between receiving approval on the first review cycle and pharmaceutical company consultation with FDA before the beginning of the final phase of human testing (the end of phase 2). The commissioner of FDA stated that “these meetings have become one of the most valuable aspects of the drug development process” (FDA News, 2006c). Deficiencies in safety assessment during the Investigational New Drug process were cited in the report as a main cause of multiple review cycles, which potentially could have been avoided if a “milestone meeting” had taken place where CDER staff could have made suggestions for improving the quality of the initial applications (FDA News, 2006c).
OTHER RELEVANT CHANGES AT THE FOOD AND DRUG ADMINISTRATION AND THE CENTER FOR DRUG EVALUATION AND RESEARCH
On November 2, 2005, FDA started requiring that drug manufacturers submit prescription drug label information to FDA in a new electronic format. That was intended to allow patients and healthcare providers to obtain information in FDA-approved package inserts (“labels”) with greater ease (FDA News, 2006c). Drug manufacturers are now required to provide FDA with accurate and up-to-date product and prescribing information in a structured product labeling that can be electronically managed. These labels will be the main source of information for a new interagency Web site, “DailyMed,” a health information clearinghouse, which will provide up-to-date information to consumers and healthcare providers free (National Library of Medicine, 2006).
In January 2006, FDA announced a change in the prescription drug format for the package insert to provide clear and concise information so that healthcare providers can make better use of the drug label to minimize risk and medical errors in their patients (FDA News, 2006c). The final rule was the first revision in 25 years and now requires that prescription information for new and recently approved products meet new criteria. The change was aimed at increasing the readability and accessibility of label information and drawing health professionals and consumers’ attention to the most important pieces of drug information before a product is prescribed. The changes include the insertion of a “highlights” section that includes concise information on the risks and benefits related to the drug, a table of contents in the label, the date of initial approval of the drug, a toll-free number, and Internet reporting information.
The labeling rule also established an important change in statutory interpretation: preempting state product liability laws on the basis of FDA’s approved label. The preamble to the labeling rule states that state laws and judicial decisions that would have the effect of finding FDA-approved labels inadequate or misleading are preempted by the federal rule (21 CFR Parts 201, 314, and 601). That position has partial support in existing case law, and FDA’s assertion of federal preemption under the new labeling rule has not yet been tested in court (National Conference of State Legislatures, 2006).
PROGRAM REVIEWS OR EVALUATIONS
In May 2006, CDER announced that it was launching an internal assessment of its Advisory Committee meeting system to establish best practices surrounding that process. The assessment will be led by senior management in CDER and will take a comprehensive look at current practices for nominating committee members, screening for conflicts of interest, choosing expertise for specific meeting topics, and utilizing Special Government Employees.
Postmarketing Study Commitments
In April 2006, FDA contracted with Booz Allen Hamilton for an evaluation of FDA’s postmarket study process (phase IV commitments) for collecting medical information (FDA Press Release, 2006). The evaluation will comment on how FDA can increase consistency in requesting, facilitating, and reviewing postmarketing commitments among centers. Ultimately, this will help FDA to request focused studies that result in the information needed to assess safety postmarket.
In August 2005, FDA and the Association of American Medical Colleges (AAMC) released the joint report Drug Development Science Obstacles and Opportunities for Collaborations, which describes an array of opportunities for scientific breakthroughs to be undertaken through collaboration to reach the goals of CPI (AAMC, 2006; AAMC et al., 2005; DeClaire, 2005). The report states that those partnerships should focus on greater sharing of knowledge, regulatory and legislative relief, earlier evaluation of drugs in humans, and improved education and training for health professionals. Some of the kinds of collaboration outlined in the report are to develop mechanisms to learn from failed drug targets, establish joint models for biomarker validation, set up a consortium to analyze and learn from failed clinical trials, and develop agreements for sharing of information restricted as intellectual property.
In November 2005, FDA, the European Commission, and the European Medicines Agency extended by 5 years a confidentiality agreement that began in September 2003 (FDA and EMEA, 2004; DeClaire, 2005; FDA et al., 2005). The types of information covered by the agreement are legal and regulatory issues, scientific advice, orphan drug designation, inspection reports, marketing authorization procedures, and postmarketing surveil-
lance. The implementation of the confidentiality agreement was planned to take place in several stages and is described in the implementation plan finalized in September 2004 (FDA and EMEA, 2004).
FDA announced that the agency would partner with the Agency for Healthcare Research and Quality (AHRQ) to launch an effort aimed at increasing research collaboration and to foster communication between the two agencies in December 2005 (FDA News, 2006b). FDA leaders stated that the collaboration will increase their understanding of health outcomes of prescription drugs, which will lead to better information to provide to the public. One component of the collaboration was assignment of a member of senior CDER leadership to a 12-month detail at AHRQ’s Center for Outcomes and Evidence as senior adviser in pharmaceutical outcomes research (FDA News, 2006b).
CRITICAL PATH INITIATIVE AND PARTNERSHIPS
In March 2004, FDA released the report entitled Innovation or Stagnation?—Challenge and Opportunity on the Critical Path to New Medical Products (the Critical Path Initiative) (FDA, 2004). The report discussed the lack of innovative technologies and science in recent years to help to make drug development less expensive and more efficient. The goal of the CPI is to make safe and effective treatments available to the public quicker by using scientific innovations. The three dimensions outlined in the CPI report are safety assessment, evaluation of medical utility, and product industrialization.
FDA called for assistance from the public, academic researchers, funding agencies, and industry to help to reach that goal because it does not believe that it can get there alone. A major objective of the CPI is to encourage new and increased collaborations among a broad array of experts to develop innovative tools.
To reach its goal, FDA has partnered with the World Health Organization, the Bill and Melinda Gates Foundation, biotechnology research firms, AAMC, and others. After receiving feedback from those and other stakeholders, FDA released the Critical Path Opportunities Report in March 2006 to identify the initiative’s six kinds of priority-targeted research. One related to safety is the use of biomarkers to predict the performance of a product during development and thus reduce uncertainties about safety or effectiveness. If the biomarkers can be identified, validated, and shown to improve health outcomes, FDA believes that these priorities “will increase efficiency, predictability, and productivity of new medical products” (FDA, 2004, 2006b).
The main element related to drug safety in the CPI is improving tools for assessing safety to detect drug safety issues as early as possible. Today,
safety issues are usually found during clinical trials or when drugs are on the market. Tests for finding safety problems earlier are few and not reliable. The CPI highlights that there are great efforts to be made and that a new safety toolkit would include the ability to predict failures due to safety before human testing in clinical trials and to demonstrate safety before a drug is on the market. The safety toolkit would lead to better safety standards by helping to predict safety performance efficiently and quickly and will decrease uncertainty.
FDA announced its partnership with the Critical Path Institute (C-Path) in December 2005 to help it to reach the goals of the CPI (FDA, 2006d). C-Path is an independent, publicly funded, nonprofit organization founded by FDA, the University of Arizona, and SRI International. It was created to fulfill the mission of the CPI, which is to “create innovative collaborations in education and research that enable the safe acceleration of the process for developing new medical products” (The Critical Path Institute, 2006). FDA leaders stated that some of the projects developed by C-Path will help to achieve many of the objectives outlined in the opportunities list discussed above.
In March 2006, shortly after the release of the Opportunities Report, FDA announced that it will be taking on an advisory role in the new Predictive Safety Testing Consortium of C-Path and five pharmaceutical companies. The partnership will “share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans” (FDA, 2006b). The collaboration is in line with the public-private partnerships stressed as a major need to improve drug development in the CPI. CDER’s J. Woodcock commented that this is a “concrete example of the power of the collaborative nature of the Critical Path Initiative.”
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