Legislation to reauthorize the Prescription Drug User Fee Act (PDUFA IV) will provide more tools and legal authority for the US Food and Drug Administration to monitor and mitigate drug risks, while also boosting user fees and extending several FDA programs. The bill, which the Congress is expected to finalize by the end of this month, implements an FDA–industry user fee agreement issued in January, and a similar plan for medical devices. Additional provisions renew incentives for manufacturers to study pediatric uses of drugs and establishes such incentives for medical devices.
They scuttle product launches and send company stocks through the floor. They steal precious years from patents and require pricey new trials. They have the entire drug industry on edge, from struggling one-hit biotechs to struggling large-cap pharmas. They're FDA approvable letters—that odd regulatory response that isn't quite an approval and isn't quite a rejection—and in the past three or four years, they've become a major part of the FDA's arsenal for dealing with (or, as many say, not dealing with) new drug applications (NDAs).
You have to admit: Mark McClellan, MD, has quite a resumé. But after you've been the commissioner of FDA and the administrator of the Centers for Medicare and Medicaid Services (CMS), what comes next?
For McClellan, who was awarded a fellowship at the AEI-Brookings Joint Center for Regulatory Studies after leaving CMS, it's about finishing what he started. Under his leadership, the think tank launched the new Engelberg Center for Health Care Reform, which seeks to find practical solutions to the very big questions surrounding the safety, affordability, and quality of medical care.
Industry insiders see McClellan as a "less talk, more action" kind of guy and hope his new post will add horsepower to moving discussions about public policy reforms into action. (After all, Medicare Part D was enacted under his watch.) Here, Pharm Exec talks to McClellan about what it will take to improve the drug safety system and the challenges that face industry and regulators alike.
The FDA is weighing whether to allow a system for electronic insert information for most prescription drugs, replacing paper Rx inserts.
Is it time to make prescribing information electronic and forgo paper package inserts for most prescription drugs? Manufacturers have long led an effort to move toward "paperless labeling," which they say could save millions of dollars. Now the Food & Drug Administration is exploring the idea with a call for comments and a recent hearing at its Rockville, Md., offices.
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Temsirolimus (Torisel, Wyeth), the first mTOR (mammalian target of rapamycin) inhibitor, was recently approved for the treatment of advanced renal cell carcinoma (RCC). "Torisel provides a new option for physicians for the treatment of renal cell carcinoma," said Cindy O'Bryant, Pharm.D., BCOP, assistant professor at the University of Colorado Health Sciences Center School of Pharmacy, Denver.
"Torisel shows promise in treating RCC—a hard tumor to treat," added James Trovato, Pharm.D., MBA, BCOP, associate professor of pharmacy practice at the University of Maryland School of Pharmacy. "It will probably be used as a first-line agent for patients with poor prognostic factors such as advanced or metastatic disease."
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The Food & Drug Administration's Medication Guide program, set up nine years ago as a way to inform patients about the risks or special issues with certain drugs, has a host of problems, according to pharmacists and other witnesses at a recent hearing. For specific drugs with serious public health concerns, the agency requires pharmacists to distribute—with each prescription and refill—written patient information that is approved by FDA and provided by the manufacturer.
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The US Food and Drug Administration plans to shut down its regional offices and some additional field facilities, a move that reflects an ever-tightening squeeze on agency funding and staff. FDA also seeks to make more efficient use of its limited resources by establishing risk-based approaches for selecting those drug-manufacturing sites most in need of frequent oversight, while reducing inspections for less risky facilities. More highly trained inspectors will be able to assess modern manufacturing systems with greater efficiency, and field staff will collaborate better with reviewers in FDA Centers to understand company quality-control systems better.
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The 2006 Guidance reveals the advantages of using electronic modalities, such as IVR, when collecting patient-reported data.
The FDA's draft guidance, "Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims," marks a formal positioning of the agency's stance regarding patient reported outcomes (PROs) in clinical trials. In publishing its guidance, the FDA has implicitly acknowledged the role of PROs and does so explicitly with statements such as: "Patients provide a unique perspective on treatment effectiveness," "Some treatment effects are known only to the patient," "Self-completed questionnaires...are often preferable to the clinician administered interview and rating." In addition, much like the EMEA,1 the FDA has acknowledged the importance and advantages of the collection of electronic patient reported outcomes (ePRO).
Regulating and monitoring clinical trials has become an increasingly complex and challenging business for the Food and Drug Administration and other government agencies that fund and oversee biomedical research. There are more clinical studies in the United States and abroad, many involving multiple sites, complex study designs, and more research participants. Many studies deal with complex biotech therapies, medical devices, and combination products and call for greater participation of vulnerable subjects, including children.
Efforts to better manage the flood of data from these research programs is generating a number of electronic record keeping and processing methods and systems that, in turn, require new rules. These developments impose new challenges for IRBs and research institutions, which continue to evolve to meet new requirements.
Who should make decisions about drug safety—FDA or patients and doctors? In this excerpt from his important new book Overdose, the renowned (and ever controversial) legal scholar Richard A. Epstein argues that the current system overvalues risk, ignores individual differences, and needlessly deprives patients of valuable treatments.
It is well known that the FDA has authority to regulate not only for purity, but also for safety and effectiveness. On the first of these questions no one challenges the role of the FDA, either inside the industry or beyond it. But the issues about safety and effectiveness raise serious questions of institutional design, which are not well handled under the current regulatory regime. The key question is this: Where should decisions about drug safety and efficacy be made, upstream by the FDA or downstream by the individual drug user, aided by professional assistance?
The development of more complex therapies to treat chronic illnesses and complex diseases warrants a whole new approach to testing and regulating prescription drugs, according to a much anticipated report from the Institute of Medicine (IOM). Several high-profile drug withdrawals and safety alerts in recent years have undermined public confidence in the Food and Drug Administration and the pharmaceutical industry and raised concerns about the agency's ability to assure the safety of critical medicines, according to a panel of health experts assessing "The Future of Drug Safety." The study says that FDA needs more funding, stronger regulatory authority, and many internal reforms to enhance its ability to monitor and implement changes in drug use after a product comes to market.
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Patient reported outcomes (PROs) are data obtained directly from patient self-reports, and their use in clinical trials is increasingly common.1 The U.S. Food and Drug Administration (FDA) recently published for comment their "Patient Reported Outcome (PRO) Measures: Use in Medical Product Development to Support Labeling Claims,"2 hereafter referred to as the PRO Guidance, to describe how they will evaluate PRO instruments. The PRO Guidance lays out the type and quality of information that clinical researchers will need to provide to justify the use of a particular PRO instrument in a trial and highlights the significance of PRO data in drug development.
By setting ground rules for use of PROs, the FDA has implicitly given credibility to PROs as the basis for evaluating drugs and biologics. Further, such guidance will eventually make for more efficient, effective, and appropriate use of these tools.
As the Food and Drug Administration celebrated its 100th birthday in June, it unveiled a major initiative for overhauling how it regulates clinical trials and protects participants in research studies. In outlining the plan for the Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) initiative at the annual meeting of the Drug Information Association (DIA), Deputy Commissioner for Operations Janet Woodcock noted that it reflects the emergence of an "increasingly large, decentralized, and global" research enterprise. She cited the need to respond to dramatic changes in the nature and conduct of clinical research characterized by:
a steady increase in the number of clinical trial studies and sites in the United States and abroad
larger trials involving many small, individual sites
proliferation of different electronic record-keeping methods and systems for data collection and processing
Like the rest of the pharmaceutical industry, Pfizer must react to FDA guidance issued June 9 that speeds the adoption of track-and-trace technology—ultimately these will be radio-frequency identification (RFID) systems—in the nation's drug-supply chain. RFID tags on medicine packages emit a unique radio signal that, unlike a bar code, can be read in bulk by electronic readers, greatly reducing the time it takes to register the arrival or departure of individual packages within a large shipment of product. Whole lots can be read on pallets without being unpacked. By checking that every package carries a unique number, the system authenticates that each package in the shipment is the same as the one that left the manufacturer's facility on a certain date.
Yes, the US Food and Drug Administration has issued its long-awaited task force report and has stated: "We continue to believe that RFID is the most promising technology for implementing electronic track and trace in the drug supply chain and that the stakeholders should move quickly to implement this technology." No, it's not a mandate, but it's clearly an "almost." The June 8, 2006 Drug Taskforce Report has the makings of becoming a high-level doctrine toward building a more secure and dependable system for safeguarding the drug supply chain.
Baby steps. With more than 24 months of in-depth research, the taskforce has been examining RFID technology and the search for the Holy Grail: an e-pedigree solution that will stem the tide of drug counterfeiting, black marketing, gray market diversion, and tampering.
The concepts for a new FDA framework for regulating manufacturing—the framework that now supports quality-by-design, risk-based regulation, process analytical technology (PAT), and their kin—began to emerge around 2002. The agency was looking for ways to loosen some of the regulatory bonds that, officials felt, constrained manufacturing progress in the United States—while finding a way to cope with the combined pressures of a growing number of products, fewer FDA inspections, diminishing financial resources, advances in technology, an emphasis on risk-based regulation, and international harmonization (1, 2).
The industry press has written a lot about those planned changes in the years since, but generally in the future tense (3, 4). The word "paradigm" was used; for once, it might have been appropriate. But, there were also raised eyebrows and an implied, "if it happens."
April 1 is usually a day to expect the unexpected. However, on April 1, 2005, the U.S. Food and Drug Administration (FDA) released the "Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics."1 The document describes the agency's "current thinking" while providing "recommendations to sponsors on endpoints for cancer clinical trials submitted to the FDA."
The following article explores the impact this guidance is having on the clinical research industry and the increasingly important role that imaging has in the assessment of cancer tumors.
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The Food and Drug Administration unveiled its long-awaited Critical Path Opportunities List in March, a summary of some 76 scientific projects that agency leaders believe can increase the efficiency, predictability, and productivity of medical product research and development. At the top of the list are a number of initiatives to identify and validate new biomarkers for clinical studies and product evaluation, along with proposals to improve clinical research practices and trial design. New statistical and computational approaches may make clinical research more informative, while computer modeling promises to avoid wasted efforts and streamline development programs.
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After months of turmoil over drug safety, vaccine shortages, and pressure to import low-cost drugs from abroad, the Food and Drug Administration faces further internal upheaval. Commissioner Lester Crawford resigned abruptly in September after only two months in the top spot, generating considerable uncertainty about the future leadership of the agency. The White House quickly named Andrew von Eschenbach, director of the National Cancer Institute (NCI) at the National Institutes of Health (NIH), as acting FDA commissioner. Von Eschenbach agreed to drop day-to-day management of NCI after being blasted for proposing to lead both NCI and FDA. He faced clear conflicts of interest in advocating for speedy access to new cancer treatments while overseeing the assessment of safety and effectiveness in those therapies. Leading legislators have urged the White House to nominate a permanent, full-time FDA commissioner.
Q. In 2005, what are the FDA's current and emerging priorities for its bioresearch monitoring program and GCP compliance?
A. In December 2004, the FDA began a major initiative to re-assess its GCP and bioresearch monitoring programs within all of its various program centers, including CDER, CBER, and CDRH. An internal FDA working group comprising representatives from throughout these centers is actively examining the entire BIMO process to re-evaluate how it works currently, what aspects of the program can be improved, how the centers can better coordinate, how the BIMO program can better focus on the highest-risk clinical studies, and how the agency can improve oversight of clinical trials involving special and vulnerable populations, including pediatric
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After months of delay, the Senate confirmed Lester Crawford in July as the official head of the Food and Drug Administration. Crawford's nomination had been put on hold as various legislators sought to pressure FDA to take action on pet issues, such as drug importing and approval of an over-the-counter version of the "morning-after" pill Plan B. Senate Finance Committee chairman Charles Grassley (R-Iowa) reflected general concerns about the agency in criticizing Crawford for not tackling drug safety failures and FDA's "structural, personnel, cultural and scientific problems."
In the end, Grassley and most Senators agreed with the leadership on both sides of the aisle that FDA would be better off with a permanent chief than without. Now it's up to the new commissioner to demonstrate that FDA decisions will be based on scientific and medical evidence —and not on pressure from industry or political leaders.
Margaret O'K. Glavin became the director of FDA's Office of Regulatory Affairs (ORA) in May 2005 and now faces a serious challenge: finding ways to manage expanding oversight responsibilities in the US and abroad for ORA's regional and district inspection teams despite shrinking resources. Glavin recognizes that ORA cannot inspect all the facilities and operations under its purview and has to determine which ones are most vital to monitor more closely with increased frequency. This determination involves reorganizing the ORA staff, revising policies, and adopting risk-based approaches for "transforming" the field inspection process.
The Food and Drug Administration recently unveiled its long-awaited Critical Path Opportunities List, which maps out a number of "scientific projects" for improving the testing and production of biotech therapies. In its March report, FDA recognizes that problems in the characterization, testing, and quality management of medical products can delay clinical trials and even completely block drug development.
At the same time, the White House officially nominated Acting Commissioner Andrew von Eschenbach to take over the top job permanently. Although von Eschenbach has provided strong support for the Critical Path initiative, his good efforts may not overcome the political issues blocking his confirmation as commissioner.