Food And Drug Administration Staff Research Articles

Pharmaceutical news and updates for renal care providers

Pharmaceutical news and updates for renal care providers

Report on Status of Regulatory Science at FDA

Frank Torti, MA, MD, MPH, was appointed as the US Food and Drug Administration (FDA)’s first Chief Scientist and Principal Deputy Commissioner on 15 May 2008. Formerly, Dr Torti was an academic oncologist and epidemiologist, most recently as Professor of Medicine and Chair of the Department of Cancer Biology at Wake Forest Medical School. His earlier career was spent at Harvard and Stanford. Dr Torti’s report, with the same title as this Editorial, was issued at the end of February 2009. It clearly builds upon two reports that emanated prior to his appointment. Presuming that this report is intended to be taken seriously, some close review and comment upon it may be justified. Dr Torti builds his mission on five principles, none of which would be questioned by anybody wishing progressive change at FDA: 1. FDA must develop an overarching scientific strategy with an accompanying implementation plan, deliverables, timetables and budget; 2. FDA scientific strategy must be pre-emptive; 3. FDA must maintain and enhance its infrastructure, core expertise and human capital; 4. FDA must tell its story; 5. FDA cannot do it alone. It would be wrong to hold these five principles to the standards of other types of organizations.While the first four might be found in a typical research university or pharmaceutical company, the last (‘‘FDA cannot do it alone’’) distinguishes the special mission of a regulatory organization, and indeed represents a desirable situation (pace those who are deluded in thinking that the Agency conspires with its stakeholders). By analogy, judges often have the warring barristers before them do much of the legal research on points of law, without ceding any judicial ground. Evidently in consultation across the various centres within FDA, a variety of priority projects are then identified in the report and are sorted against these five principles. Here, the report is somewhat ‘retro’ and repetitive of what we have all known for a few years already: for example, overarching scientific priorities include rapid detection of pharmacovigilance signals, development of biomarkers, more efficient clinical designs and analyses, etc. Microbial contamination (a highvisibility issue for both foods and drugs in the US at the moment) appears more than once. An original idea is that an ‘omics’ czar is proposed, to deal with genomic, proteomic andmetabolomic issues across centres and reviewing divisions. This could well be seminal for the development of personalizedmedicine and is consonant with an FDA Science Board emphasis on differential drug response between racial groups. Combination product coordination also receives attention. However, its guru will only be an FDA fellow (essentially a 2-year post-graduate internship within the Agency). Outside interactions (‘‘FDA cannot do it alone’’) are thought to benefit especially the areas of drug-induced liver injury, nano-engineered products, and the development of centres of excellence in collaboration with academia. However, the report states: ‘‘Small biotechnology firms represent a flexible resource. They are operationally and scientifically nimble, and often have capability to devote a large proportion of human capital to a single project. Biotech firms that have an interest in partnering to resolve mission-critical FDA questions will be identified and engaged through contracts and other funding mechanisms.’’ Another opinion might be that the FDA seems oblivious of how small companies work. First, the present financial situation makes it unlikely that there will be any substantive venture capital for biotech for the next 5 years. Moreover, those few companies that survive might be expected to have their own mission-critical questions that will take priority over the FDA’s. It is also telling that this report refers to FDA staff as being ‘‘well-trained physicians and scientists’’, and even that FDA Fellows are ‘‘highly qualified and selected scientists’’; meanwhile, the biotech companies who are going to provide all this help evidently contain ‘‘human capital’’. EDITORIAL Pharm Med 2009; 23 (1): 1-2 1178-2595/09/0001-0001/$49.95/0

FDA Blamed for Poor Monitoring of Off-Label Drug Promotion

FDA Blamed for Poor Monitoring of Off-Label Drug Promotion

Drug's Availability Doesn't Mean FDA Has Approved It

Back to table of contents Previous article Next article Professional NewsFull AccessDrug's Availability Doesn't Mean FDA Has Approved ItJun YanJun YanSearch for more papers by this authorPublished Online:16 Nov 2007https://doi.org/10.1176/pn.42.22.0005There may be thousands of drug products being prescribed and dispensed to patients in the United States that have never been reviewed by the Food and Drug Administration (FDA) for safety and efficacy or approved for marketing. The agency is now taking steps to address the potentially large problem.In June 2006, the FDA released a guidance document, “Marketed Unapproved Drugs—Compliance Policy Guide,” to clarify the rules regarding drugs on the market that have not been reviewed or approved by the agency's normal process and the agency's plan to enforce them.Many of these unapproved drugs are advertised and listed in reference books such as the Physicians' Desk Reference, prescribed by physicians, and dispensed or sold to patients, according to the FDA guidance document. Physicians and pharmacists are usually not aware of the unapproved status of these drugs, which can be distributed based on a 10-digit number known as the National Drug Code (NDC). The NDC number is issued to all types of drug products, including unapproved investigational drugs, and does not guarantee a drug's approval status. These products' labeling information does not distinguish their approval status, nor is the labeling necessarily reviewed by the FDA for safety claims and indications.The FDA says on its Web site that most of these products remain on the market illegally for “a variety of historic reasons.” Most became available before the Federal Food, Drug, and Cosmetic Act was revised in the 1960s to require that a new drug be evaluated by the FDA for efficacy as well as safety. Before these regulations, new drugs only needed to be shown as safe, and drugs deemed the same or similar to approved drugs needed no independent review and approval process by the agency. The labels of these products may not conform to current regulatory standards and may carry unapproved claims and indications. Although the FDA had contracted with the National Academy of Sciences/National Research Council to evaluate the effectiveness of thousands of products approved only for safety between 1938 and 1962, not all products have gone through the approval process.Even the drug products deemed illegal have not all been forced off the market. Other provisions in the regulations have allowed older drugs without labeling updates to slip through the cracks.It is unknown how many currently marketed drugs are unapproved, and the agency does not maintain a complete list of these products. The guidance estimated that “several thousand drug products are marketed illegally without required FDA approval” today and admits that the agency is“ unable to take action immediately against all. . .illegally marketed products” because of a lack of resources.Since the release of the guidance last year, the FDA has been systematically issuing sanctions against certain unapproved products by demanding their withdrawal from the market or convincing some manufacturers to go through the official process by filing a New Drug Application for the agency's review in order to legalize their products and update the product labeling. A short list of drugs and manufacturers against which enforcement actions have already been taken is posted on the FDA's Web site.The guidance document claims that the enforcement priorities are given to drugs that have potential safety risks, lack evidence of effectiveness, are fraudulently promoted and sold, “present direct challenges to the new drug approval and [over-the-counter] drug monograph systems,” or are reformulated to evade FDA enforcement action. Priority is also given to unapproved new drugs that violate the regulations in other ways.In 2006, unapproved products containing quinine and carbinoxamine with unapproved labeling were targets. This September, the agency announced that it will take “enforcement action” against manufacturers of unapproved hydrocodone-containing cough syrups, citing reports of medication errors due to formulation changes in the unapproved products and confusion over their brand names. The agency is also concerned that “no hydrocodone cough suppressant has been established as safe and effective in children under 6 years of age, and some of these unapproved products carry labels with dosing instructions for children as young as 2 years old,” warned Steven Galson, M.D., M.P.H., director of the FDA's Center for Drug Evaluation and Research in a press release.The FDA Web page lists selected drugs and companies that have been cited for enforcement actions, but includes no psychiatric drugs. However, the FDA has not released a complete list of all unapproved drug products on the market. Psychiatrists may be treating patients who are taking, for example, unapproved hydrocodone, levothyroxine, and quinine products (for restless legs syndrome).Additional information about unapproved drugs and FDA actions is posted at<www.fda.gov/cder/drug/unapproved_drugs/default.htm>.“ Guidance for FDA Staff and Industry: Marketed Unapproved Drugs—Compliance Policy Guide” is posted at<www.fda.gov/cder/guidance/6911fnl.pdf>.▪ ISSUES NewArchived

Carotid Stents: Unleashed, Unproven

Primarily on the basis of data derived from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial,1 the US Food and Drug Administration (FDA) has approved the use of carotid stents (CASs) in high-risk patients. The SAPPHIRE trial was published and much heralded as a randomized trial demonstrating that CASs were not inferior to carotid endarterectomy (CEA). Yet, the more recent Endarterectomy Versus Angioplasty in Patients with Symptomatic Carotid Stenosis randomized trial of CASs compared with CEA had to be stopped because the stroke rate with stents was so high that it triggered the safety guidelines of the study design.2 How can we explain the striking difference in outcome between these 2 studies, and how did it happen that the FDA was so convinced of the quality and validity of the SAPPHIRE trial that it granted approval for CASs? An examination of the SAPPHIRE trial—its conduct, data collection and analysis, the circumstances of publication, the presentation to the FDA Advisory Panel, and its consequent approval—is the primary focus of this article. This is a case study of the flaws in our system for the evaluation and approval of medical devices that warrant serious reflection on our ability to properly create and act on accurate information and live up to our commitment to evidence-based decision making. Response by Samuelson et al p 1601 As it now stands, existing studies leave us with the unfortunate but not unreasonable conclusion that no scientific basis exists for the use of CASs as approved by the FDA, and in the absence of change, there is every reason to doubt the capability of our current system to protect the public from unnecessary risk in the future. Although this article focuses on just 1 example of how our systems …

FDA Orders New Guides for ADHD Prescriptions

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessFDA Orders New Guides for ADHD PrescriptionsJim RosackJim RosackSearch for more papers by this authorPublished Online:16 Mar 2007https://doi.org/10.1176/pn.42.6.0001aMedications prescribed to treat attention-deficit/hyperactivity disorder (ADHD) must be accompanied by a patient medication guide, the U.S. Food and Drug Administration (FDA) said last month. The announcement came a year after two advisory committees urged the agency to provide more complete and clear information on the benefits and risks of taking medications most commonly prescribed to treat ADHD (Psychiatric News, April 21, 2006).There are 14 amphetamine and methylphenidate preparations and one nonstimulant medication, atomoxetine, approved for the treatment of ADHD. Draft medication guides (“med guides”) for each of the medications are now posted on the FDA's Web site (see the link at end of article). They are aimed at prescribers, adult patients, and the parents or caregivers of children taking the medications.The final med guides should be available in pharmacies within the next three to four months, according to Thomas Laughren, M.D., director of the FDA's Division of Psychiatry Products.The language in the draft med guides was written by FDA staff. FDA officials have requested that each manufacturer review the drafts, and companies often suggest changes. The final content is negotiated between the FDA and the manufacturers of each medication.The med guides use lay language to point out two specific areas of concern associated with taking stimulant medications: the potential for an increased risk of serious cardiovascular adverse events, including heart attack, stroke, and sudden death; and the potential for an increased risk of adverse psychiatric events such as the worsening of existing symptoms or the development of treatment-emergent mania, delusions, or hallucinations.In a box at the beginning of each med guide is the question, “What is the most important information I should know about [medication name]?” For the amphetamines and methylphenidate preparations, the box notes that spontaneous reports have occurred with patients taking stimulant medications, concerning “heart-related problems” and “mental (psychiatric) problems.”The box goes on to warn that sudden death, heart attacks, strokes, and increases in heart rate and blood pressure have all been reported. Patients and parents are urged to discuss with their doctor any heart problems that they, the child, or their immediate relatives have and are told that their doctor should check for heart problems before starting the medication.In addition, patients and parents are instructed to call their doctor immediately if “any signs of heart problems such as chest pain, shortness of breath, or fainting” develop while taking the ADHD medication. Similarly, they should be on the lookout for “new or worse behavior and thought problems, new or worse bipolar illness, or new or worse aggressive behavior or hostility.” Parents are specifically told to watch for “new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious), or new manic symptoms” in children and teenagers.The med guide for atomoxetine carries the same warnings about“ heart-related problems” and “new mental (psychiatric) problems in children and teenagers”; however, these warnings come much later in the med guide. Because atomoxetine is a dual reuptake inhibitor (serotonin/norepinephrine reuptake inhibitor, or SNRI) rather than a stimulant, the most prominent warning, listed at the beginning of the atomoxetine med guide, concerns “suicidal thoughts and actions in children and teenagers.”The FDa's Laughren told reporters at a press briefing last month that the agency decided to follow the advice of its Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee, even though there is no documented direct link between the medications and the spontaneous adverse events of cardiovascular or psychiatric problems.Laughren noted that the advisory committees reviewed reports of cardiovascular events associated with patients who took ADHD medications. There were 39 deaths and 54 reports of “serious but nonfatal” cardiac events. The information “arose entirely from spontaneous reports [through the agency's MedWatch drug surveillance system].” Many of the cases, he noted, involved young patients with unknown cardiac disease or congenital defects or patients taking multiple medications.“While the possibility exists,” Laughren said, “that these events are related to the underlying cardiovascular disease and not the drug, [the advisory committees] advised us to go ahead and alert the public to the possibility that the drug might have had a role.”Evidence of a “causal link” between the ADHD medications and psychiatric adverse events “is stronger than for the cardiovascular events,” said Laughren. He noted that reports of treatment-emergent mania or psychotic symptoms arose not just from MedWatch, but also from a pooled analysis of clinical-trials data.More information and links to the draft med guides are posted at<www.fda.gov/cder/drug/infopage/ADHD/default.htm>.▪ ISSUES NewArchived

Counterpoint: Food and Drug Administration Guidance for C-Reactive Protein Assays: Matching Claims with Performance Data

Dr. Rifai and coauthors seem to have misunderstood the guidance proffered by the US Food and Drug Administration (FDA)1 and the laboratory safety tip addressing the issue of matching claims with performance data for C-reactive protein (CRP) assays. The FDA believes that different claims for CRP require very different data sets and different performance criteria to support differing intended uses. FDA premarket guidance proposals are written to benefit companies and FDA reviewers regarding recommendations for studies that support premarket submissions for medical devices in the United States. They are not meant to be clinical practice guidelines; however, FDA guidelines are meant to be based on sound science, committed to truth in labeling, and intended to help to ensure the safety and effectiveness of medical devices for the promotion of public health. The driving force behind FDA premarket assay reviews is based on the indications for use of a given assay. For regulatory purposes, the distinction between CRP assays, high-sensitivity (hs)CRP assays, and cardiac (c)CRP assays lies with the Indications for Use. In the Guidance for Industry and FDA Staff: Criteria for Assessment of C-Reactive Protein (CRP), High Sensitivity …

MAOI Skin Patch May Come With Fewer Warnings

Back to table of contents Next article Government NewsFull AccessMAOI Skin Patch May Come With Fewer WarningsJim RosackJim RosackSearch for more papers by this authorPublished Online:16 Dec 2005https://doi.org/10.1176/pn.40.24.0001The lowest dose of a new transdermal formulation of selegiline, a monoamine oxidase inhibitor (MAOI) antidepressant, should not be required to carry long-standing warnings about avoiding dietary intake of foods high in tyramine, an advisory panel of the U.S. Food and Drug Administration (FDA) told the agency.Joseph Berger, M.D. (left), discusses an action paper with colleague Ray Freebury, M.D., at last month's meeting of the APA Assembly. Berger and Freebury are the representatives from the Ontario District Branch. See page Original article: 9 for coverage of the meeting.David HathcoxBy a vote of 7-4, members of the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) recommended in October that the 20 mg skin patch be marketed without the restrictions found on all MAOIs marketed to date. In a second vote by the same count, PDAC members said it was permissible to market the 20 mg patch without dietary restrictions, even if two higher doses carried the warnings. Final approval is expected in the first half of 2006.The selegiline transdermal patch—to be marketed by Somerset Pharmaceuticals under the trade name Emsam—will be available in 20 mg, 30 mg, and 40 mg strengths. Somerset had already reached agreement with the FDA that the two higher doses will carry the standard dietary warning; however, the company said the lowest dose was safe and should be marketed without any need for patients to watch their diets.Because an internal FDA review of the data concluded that all three doses should carry dietary restrictions, the agency chose to put the issue before the advisory committee.The PDAC's recommendations are not binding on the agency, which will make a final decision on the labeling for the patches within the next few months. Somerset (a joint venture of Mylan and Watson Pharmaceuticals) received tentative FDA marketing approval for 20 mg, 30 mg, and 40 mg doses of selegine in January 2004; however, the agency expressed concern about the safety of the drug and the need for dietary restrictions. Somerset filed its response to those concerns this past May 26.Selegiline is a nonselective MAOI, inhibiting not only the MAO-B enzyme in the central nervous system, but also MAO-A elsewhere in the body. In the digestive tract, MAO-A normally metabolizes tyramine, a dietary amine that is found in high concentrations in foods such as aged cheese and red wine.The breakdown of tyramine in the gut prevents significant amounts of it from being absorbed and circulated throughout the body. Tyramine is a potent pressor— leading to constriction of blood vessels— which ultimately results in increased blood pressure. High amounts of tyramine can lead to hypertensive crises, resulting in stroke, heart attack, and even death.Because the medication is absorbed from the skin patch and bypasses the gut wall, it is thought that transdermal selegiline will have a significantly reduced effect on MAO-A in the digestive tract. In addition, at lower doses, selegiline is thought to inhibit MAO-B preferentially, while at higher doses both A and B isoenzymes are effected. With significantly reduced inhibition of digestive tract MAO-A, dietary restrictions would not be necessary, the company argued.Thomas Laughren, M.D., head of psychiatry products at the FDA, wrote in a memo to PDAC members, “Having to worry about diet is a major disincentive to using the orally available MAOIs in the U.S.”Appearing before the committee, FDA staff reviewer Greg Dubitsky, M.D., strongly argued that the clinical trial data regarding tyramine sensitivity in patients wearing selegiline patches was highly variable, and for that reason said he could not conclude that it was safe to market the 20 mg dose without dietary restrictions. He urged that dietary warnings be put on the labels of all three doses of the patch.In the end, though, the majority of PDAC members were not swayed by Dubitsky's argument.“I am convinced that there is no harm signal in either the clinical trials data that were represented or the more extensive database for the use of Eldepryl [selegiline in pill form],” said Wayne Goodman, M.D., PDAC chair and a professor of psychiatry at the University of Florida.Goodman said that “benefit is clearly an issue here,” noting the unique new dose formulation will present patients with an entirely new option. “We do have other MAOIs on the market,” he said,“ but it's clear to me that this is going to produce far less risk than our existing medications.”More information on the PDAC's consideration of Emsam is posted at<www.fda.gov/ohrms/dockets/ac/05/briefing/disclaimer.htm>.▪ ISSUES NewArchived

What’s Wrong with This Label?

What’s Wrong with This Label?

FDA Officials Divided Over Need for Policy Change

FDA Officials Divided Over Need for Policy Change

Approval Times For New Drugs: Does The Source Of Funding For FDA Staff Matter?

The Food and Drug Administration (FDA) has been criticized for injudicious and excessively rapid approval of new drugs as a result of pharmaceutical industry influence. Many critics focus on the Prescription Drug User Fee Act (PDUFA) of 1992, which augmented the FDA's budget through the charging of user fees. We assess the effect of FDA staffing patterns and attributes of submitting firms on approval times for 843 new drug applications (NDAs) submitted between 1977 and 2000. NDA review times shortened by 3.3 months for every 100 additional FDA staff. The amount of funding for FDA staff appears to be a much more important influence on NDA review time than the source of funding.

FDA Seeks Swifter Approval of Drugs for Some Life-Threatening or Debilitating Diseases

THE FOOD AND DRUG Administration (FDA) is seeking to accelerate approval of drugs for patients with life-threatening or debilitating diseases. Obvious candidates are drugs against acquired immunodeficieny syndrome (AIDS) and anticancer treatments. The agency issued an interim rule, published in theFederal Register, that expands Phase II clinical trials to provide enough data on safety and efficacy of designated drugs to enable them to bypass Phase III studies and be considered for approval. Although there are provisions for comment on the rule, it actually took effect on the publication date a month ago. If the FDA staff considers it necessary, such drugs would continue to be monitored by a postmarketing surveillance system. This will be decided on a case-by-case basis. To further speed the approval process, the agency will convene advisory committees as needed to consider the data from the expanded Phase II studies. Studies ready for consideration thus won't

Regulation of essential nutrient additions to animal diets (selenium -- a model case).

Responsibility for regulation of essential nutrient additions to animal diets has been assumed by the Food and Drug Administration (FDA) through internal interpretation of the Federal Food, Drug and Cosmetic Act. Thus, these substances are regulated as food additives or through qualification for the generally recognized as safe (GRAS) list. Although essential nutrients, such as selenium, are not optional additives to animal diets that are demonstrably deficient (if animal health and welfare are of concern), supplementation with unapproved nutrients places one in violation of FDA interpretation of law. Selenium was established as a dietary essential in 1957, and practical problems with a deficiency of this nutrient were recognized soon after. Research was begun in 1967 specifically to gain FDA approval for selenium as a dietary supplement. Approval was granted for selenium supplements to swine and certain poultry diets in 1974. At that time, FDA staff members reported that the inability to supplement these diets with selenium had caused annual losses of over $82 million. Annual losses to the beef cattle, dairy cattle and sheep industry were estimated in 1975 at nearly $545 million. In a coordinated effort (initiated in 1975) involving scientists at nine United States universities and the FDA, data were gathered leading to approval in 1979 of selenium supplements for ruminants. The cost of the effort to meet regulatory requirements for selenium has been estimated at more than $1 million. Since this nutrient is not a proprietary product, this effort has been made largely at public expense. The inability to supplement selenium-deficient diets prior to FDA approval has cost hundreds of millions of dollars.