Food And Drug Administration Website Research Articles

Outcomes of LASIK for Myopia With FDA-Approved Lasers

To report expected outcomes of laser in situ keratomileusis (LASIK) for myopia and myopic astigmatism from existing US Food and Drug Administration (FDA) data. Data from Summaries of Safety and Effectiveness for each of the 12 lasers approved by the FDA for LASIK for myopia or myopic astigmatism between 1998 and 2004 were recorded from the FDA Web site. The Cochran-Armitage test for trend was used to determine whether improvements in outcomes occurred with laser technology changes. For all patients, there was a statistically significant trend toward improvement with improved laser technology in the proportion of patients with uncorrected visual acuity (UCVA) of 20/20 or better, UCVA of 20/40 or better, results within +/-0.50 D of intended correction, results within +/-1.00 D of the intended correction, and night vision symptoms (all P < 0.0002). Because there were preoperative differences across laser types, subgroup analyses were also completed. The results for subgroup analyses (high myopia, low to moderate myopia, spherical myopia, and myopic astigmatism) for visual acuity and refractive error outcomes were similar to results for analyses for all groups combined. Conversely, there was no difference across laser types in the proportion of patients who experienced dry eye symptoms or for the proportion of patients with low to moderate myopia who experienced night vision symptoms that were worse or significantly worse than before LASIK. LASIK provides excellent visual acuity and refractive error outcomes. Night vision and dryness symptoms still occur in a significant proportion of patients. Future studies should seek to determine whether additional changes in technology, patient selection criteria, or postoperative treatment could reduce or eliminate these symptoms.

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

Drug Interaction Studies: Study Design, Data Analysis, and Implications for Dosing and Labeling

One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose-response studies, and drug-drug interactions.

Lapses at the New England Journal of Medicine

Lapses at the New England Journal of Medicine

Pediatric Drug Development in Anesthesiology: An FDA Perspective

Bob A. Rappaport, MD In their editorial entitled “Pediatric Research and Scholarship,” Tobin et al. (1) question whether the Food and Drug Administration (FDA) has taken an acceptably proactive role in efforts to encourage high quality clinical trials of drugs in the pediatric patient population when those studies are performed by individual academic investigators. In particular, they question the obligation of academic investigators to abide by federal regulations when conducting small clinical trials with drugs not yet approved for the pediatric population. In response, we will review the role of the FDA in clinical research conducted by individual academic investigators, summarize recent progress in pediatric drug development, and offer suggestions to academic investigators who wish to perform these types of drug trials.

Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?

6026 Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs. No significant financial relationships to disclose.

Prescription Drug Labels to Get New Look, Clearer Language

Back to table of contents Previous article Next article Government NewsFull AccessPrescription Drug Labels to Get New Look, Clearer LanguageMark MoranMark MoranSearch for more papers by this authorPublished Online:19 May 2006https://doi.org/10.1176/pn.41.10.0001aFor the first time in 25 years, the Food and Drug Administration (FDA) is requiring a major revision to the format of information in prescription drug package inserts.Effective in June, any new agent and any new indication for a drug already on the market must include the newly reformatted labeling.Moreover, labeling for all drugs approved within the last five years will be reformatted according to a phase-in schedule: labels for drugs approved within the last three years will have three years to conform to the new format, according to Thomas Laughren, M.D., director of the Division of Psychiatry Products at the FDA's Center for Drug Evaluation and Research.Those drugs approved between three and five years ago will have a longer time before the new labeling will be required, Laughren told Psychiatric News.Laughren said the labeling change is the result of several years of discussion with industry and clinicians about the increasing complexity of information in package inserts for prescription drugs.“We have held a number of focus groups with physicians and public meetings and have solicited written comments from groups including the pharmaceutical industry,” he said. “We have gotten some feedback that the existing labeling has gotten too complicated, too long, and too difficult to find important information.”The most prominent change in the labeling requirement is the addition of a section titled “Highlights.”“This is a half-page summary at the start of the labeling that summarizes key information, including a black-box warning if there is one,” Laughren said.In addition, the new labeling will include a table of contents following the “Highlights” section that will have hyperlinks to the pertinent text referenced in the table. The latter is an accommodation to the movement toward e-prescribing.“The hyperlinks should make it particularly easy for clinicians to find pertinent information as we move into the electronic era,” Laughren said. “What we have learned from clinicians in their comments to us is that the way they use the labeling is as a reference source—that is, they tend to go to the specific section that has the information they need. The hyperlinks will allow prescribers to do just that.”According to information about the labeling change on the FDA's Web site, black-box warnings—such as those required on medications for ADHD—will still appear in the labeling even though the warnings are summarized in “Highlights.”“As with all information in `Highlights,' the boxed warning... is a summary, not a duplication of the full boxed warning in the full prescribing information,” according to the FDA. “It typically will be in a bulleted format, limited to 20 lines, and will refer to more detailed information, including the complete boxed warning and other sections of the FPI. Because `Highlights' is one-half page in length and the table of contents follows, [the boxed warnings in `Highlights'] will rarely, if ever, appear on the same page of the prescribing information as the full boxed warning. The FDA believes a summarized boxed warning in `Highlights,' with references to more detailed information, is the most effective way to communicate critical safety information to health care professionals.”Laughren said he did not foresee any changes to labeling that were specific to products for psychiatric patients beyond those changes that will be applicable to products prescribed by all clinicians.Other significant changes, in addition to the “Highlights” section and the table of contents, are easy access to the date of initial product approval, making it easier to determine how long a product has been on the market, and inclusion of a toll-free number and Internet reporting information for suspected adverse events. This is an attempt to encourage more widespread reporting of suspected side effects.Other government officials agree with Laughren that the new labeling is aimed ultimately at reducing medication errors.“Providing health care professionals and patients with clear and concise information about prescriptions will help ensure safe and optimal use of drugs, which translates into better health outcomes for patients and more efficient delivery of health care,” said Mike Leavitt, secretary of Health and Human Services, in a statement about the labeling change. “By improving the package insert to make it more useful for health care providers in their day-to-day clinical practice, we are making it easier for them to explain the benefits and risks of medications for their patients.”More information about the labeling change is posted at<www.fda.gov/cder/regulatory/physLabel/default.htm>.▪ ISSUES NewArchived

The SSRI Trials in Children: Disturbing Implications for Academic Medicine

The recent announcement by the Food and Drug Administration (FDA) requiring pharmaceutical companies to warn patients about the increased likelihood of suicidal thoughts when taking antidepressants was largely due to the recent availability of data that had gone unreported in the original research reports. The current article is a summary of the comparison between the published literature and the recently released data available on the FDA web site, with a focus on Prozac, Paxil, and Zoloft. The discrepancies between the two versions suggest that the scientific community was not given enough information in the published medical literature to make adequately informed decisions about the optimal method for treating emotionally distressed children. There are many voices that want to blame the FDA for its role in the widespread use of these medications. The current article focuses on the role that academic medicine played in the process whereby these medications became so widely accepted.

A Systematic Review of the Efficacy and Safety of Atypical Antipsychotics in Patients with Psychological and Behavioral Symptoms of Dementia

Although the Food and Drug Administration (FDA) has not approved atypical antipsychotics for use in patients with dementia, they are commonly prescribed in this population. Recent concerns about increased risk of cerebrovascular events and mortality have led to warnings. A systematic review was conducted to assess the benefits and harms of atypical antipsychotics when used in patients with behavioral and psychological symptoms of dementia. Electronic searches (through March 2005) of the Cochrane Library, Medline, Embase, and PsycINFO were supplemented with hand searches of reference lists, dossiers submitted by pharmaceutical companies, and a review of the FDA Website and industry-sponsored results database. Using predetermined criteria, each study was assessed for inclusion, and data about study design, population, interventions, and outcomes were abstracted. An overall quality rating (good, fair, or poor) was assigned based on internal validity. The evidence for olanzapine and risperidone supports their effectiveness compared with placebo. Short-term adverse events were similar to placebo. Risperidone had no advantage over haloperidol on efficacy measures in the better-quality studies. Risperidone had an advantage over haloperidol on some measures of extrapyramidal symptoms. Evidence for the other atypical antipsychotics is too limited to assess efficacy and safety. Trials were short term and conducted in highly selected populations. The potential for increased risk of cerebrovascular adverse events and mortality is a serious concern. To make judgments about when the benefits of atypical antipsychotics outweigh the potential harms, clinicians need more information. Additional data from existing trials and more-complete reporting of trial results could provide this information.

ASGE Technology Status Evaluation Report: disposable endoscopic accessories

ASGE Technology Status Evaluation Report: disposable endoscopic accessories

From the FDA

DRUG labeling is of vital importance in guiding the safe and effective use of approved drugs. Drug labels represent the most visible expression of months or years of scientific review by physicians and scientists at the U.S. Food and Drug Administration (FDA), and they are also fundamental to the purpose and mission of the FDA. Creation of the FDA dates to the 1906 passage of the Food and Drugs Act, which prohibited the manufacture and interstate shipment of adulterated and misbranded foods and drugs.† A 1937 disaster, in which more than 100 people died after ingestion of Elixir Sulfanilamide, precipitated the Federal Food, Drug, and Cosmetic Act of 1938, which, for the first time in U.S. history, required demonstration of safety before marketing new drugs. Elixir Sulfanilamide contained diethylene glycol and had never been tested for safety. In 1960, a marketing application for the drug thalidomide was submitted to the FDA. Withstanding enormous pressure from the applicant, FDA reviewers, including Frances Kelsey, M.D., Ph.D., a medical officer at the Center for Drug Evaluation and Research at the FDA (Washington D.C.),‡ determined that inadequate data were available to support the safety of the drug product despite its already widespread use throughout the rest of the world. The application was not approved. After thousands of children in 46 countries were born with deformities as a consequence of thalidomide use, leaving the United States relatively unscathed, a political movement for tighter drug controls in the United States gained popular support. The Drug Amendments of 1962 were the first to require demonstration of effectiveness before marketing, recognizing that the assessment of safety must also consider benefit. Since 1962, more than a thousand prescription drugs have had their labeling changed or have been taken off the market to reflect the scientific evidence (or lack thereof) documenting their safety and/or effectiveness.§ Section 505 of the Federal Food, Drug, and Cosmetic Act (21 USC 355) currently specifies that approved drugs must be safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling. Current regulations stipulate the following labeling requirements:

Pemetrexed in Malignant Pleural Mesothelioma

This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New Drug Application for the treatment of malignant pleural mesothelioma (MPM). The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed. In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia. Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m(2) cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.

FDA Vows to Improve Drug-Safety Assessments

FDA Vows to Improve Drug-Safety Assessments

Withdrawal of article by the FDA after objection from medtronic

Withdrawal of article by the FDA after objection from medtronic

Suicidality as a Possible Side Effect of Antidepressant Treatment.

PHYSICIANS RESPOND TO THE FDA PUBLIC HEALTH ADVISORY ON WORSENING DEPRESSION AND SUICIDALITY IN PATIENTS BEING TREATED WITH ANTIDEPRESSANTS: On March 22, 2004, the U.S. Food and Drug Administration (FDA) issued a health advisory informing the public that manufacturers of several popular antidepressants have been asked to include a warning statement on product labeling. This warning statement recommends that antidepressant-treated patients-both children and adults-should be closely monitored for worsening of depression or emergence of suicidal behavior. The full text of the advisory, along with supporting information and presentations from the February 2004 meeting on which this advisory was based, can be found on the FDA's Web site at http://www.fda.gov/cder/drug/antidepressants/default.htm. Recently, the CME Institute, as a service to its members-you, the readers of this journal-and Larry Culpepper, M.D., Editor in Chief of the Primary Care Companion, assembled a group of psychiatrists and primary care physicians to discuss the FDA advisory and advise clinicians how it will affect their treatment of depressed patients. Their discussion and recommendations appear here. Faculty affiliations and disclosures appear at the end of this Commentary.

FDA Rejects Citizen Petitions for Over-the-Counter Hearing Aids

FDA Rejects Citizen Petitions for Over-the-Counter Hearing Aids

Over-the-Counter Hearing Aids

Over-the-Counter Hearing Aids

Cochlear Implant Recipients Have Increased Risk of Meningitis

Cochlear Implant Recipients Have Increased Risk of Meningitis

Bar Codes Coming To Medications Near You

Back to table of contents Previous article Next article Government NewsFull AccessBar Codes Coming To Medications Near YouChristine LehmannChristine LehmannSearch for more papers by this authorPublished Online:4 Apr 2003https://doi.org/10.1176/pn.38.7.0017aMedication errors are among the most common preventable mistakes in health care, according to a 1999 Institute of Medicine report. Experts have estimated that more than one million serious errors related to medication occur annually in hospitals alone.In an effort to reduce medication errors, the Food and Drug Administration (FDA) proposed two new rules last month as part of the agency’s strategic initiative to curb adverse events related to the products it regulates, according to an HHS press release.Tommy Thompson, secretary of Health and Human Services, announced the proposed rules last month. “These proposals are key steps in reducing medication problems through state-of-the-art technology,” said Thompson in the press release.The first rule would require bar codes on all prescription drugs, over-the-counter drugs packaged for hospital use, and vaccines.Thompson said that bar codes are already widely used in hospitals and other health care settings. The code would at minimum contain the National Drug Code (NDC) number, which identifies the drug, its strength, and dosage form.The FDA seeks comment on whether to add information such as lot number and expiration date.“The bar code, when used with a bar code scanner and computerized patient information systems, can prevent many medication errors, including giving the wrong drug to a patient, giving the drug to a patient who is allergic to it, giving the wrong dose or at the wrong time, or using the wrong route of administration, for example, by injection rather than by mouth,” said Thompson in the release.Thompson also announced a second FDA proposed rule designed to revamp the safety reporting requirements for medications. The rule would require companies that produce medications to submit to the FDA, within 15 calendar days, all reports they receive of actual and “near-miss” medication errors in the United Sates, according to the press release.One example of a “near-miss” is when a pharmacist selects the wrong medication because of a similar sounding name but catches the error prior to dispensing the medication.” The company would be required to report the potential error to the FDA if the pharmacist reported to the company what happened, according to the release.The proposal is also intended to promote uniform reporting standards among regulatory agencies in the United States and abroad.In addition, the proposal would require the submission of all suspected serious reactions for blood and blood products on the market.The proposal clarifies the kind of data needed in various safety reports to “lessen industry’s reporting burdens especially for certain suspected adverse reactions that are not serious. Companies can focus on producing high-quality reports for serious suspected adverse reactions, which potentially have a much greater public health impact,” said Thompson in the release.Fact sheets on both proposed rules and other related materials are posted on the FDA Web site at www.fda.gov/oc/initiatives/barcode-sadr. The public can submit comments on the proposed barcode rule until June 14 and on the safety reporting requirements until July 14 (90 and 120 days respectively from the March 14 publication in the Federal Register). Comments can be submitted online by accessing www.accessdata.fda.gov/scripts/oc/dockets/comments/commentdocket.cfm and clicking on “02N-0204—Bar Code Label Requirements for Human Drug Products” and “00N-1484—Safety Reporting Requirements for Human Drug and Biological Products.” Written comments on both proposed rules should be submitted by the same deadlines to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md. 20852. ▪ ISSUES NewArchived

Med Check

Med Check