Gaps, tensions, and conflicts in the FDA approval process: implications for clinical practice.
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Despite many successes, drug approval at the Food and Drug Administration (FDA) is subject to gaps, internal tensions, and conflicts of interest. Recalls of drugs and devices and studies demonstrating advantages of older drugs over newer ones highlight the importance of these limitations. The FDA does not compare competing drugs and rarely requires tests of clinical efficacy for new devices. It does not review advertisements before use, assess cost-effectiveness, or regulate surgery (except for devices). Many believe postmarketing surveillance of drugs and devices is inadequate. A source of tension within the agency is pressure for speedy approvals. This may have resulted in "burn-out" among medical officers and has prompted criticism that safety is ignored. Others argue, however, that the agency is unnecessarily slow and bureaucratic. Recent reports identify conflicts of interest (stock ownership, consulting fees, research grants) among some members of the FDA's advisory committees. FDA review serves a critical function, but physicians should be aware that new drugs may not be as effective as old ones; that new drugs are likely to have undiscovered side effects at the time of marketing; that direct-to-consumer ads are sometimes misleading; that new devices generally have less rigorous evidence of efficacy than new drugs; and that value for money is not considered in approval. (+info)
Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept.
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OBJECTIVES: To describe a nationwide system for postmarketing follow up of new antirheumatic drugs in Sweden, and to analyse safety and effectiveness in an etanercept treated patient cohort. METHODS: Etanercept became available in Sweden for prescribing on a named patient basis in 1999. All patients treated were included in a follow up of intensified adverse event reporting and recording of clinical outcome during 24 months, according to the EULAR core set. RESULTS: The mean (SD) disease activity score (DAS 28) value at inclusion among 820 patients recruited on a named patient basis during year 1 was 5.99 (1.19). After two years, 21% (n = 172) of these patients had discontinued the treatment. Of the remaining 648 patients, 68% (n = 442) responded to the treatment. However, in 55% of the responders, the disease activity was intermediate or high (mean DAS 28, 3.37 (1.20)). In all, 540 adverse events were reported in 421 adverse drug reaction (ADR) reports, in 294 patients. The events in 80 reports (19%) were serious. Twenty two per cent of the events were infections, of which 24% (n = 29) were serious. The incidence of serious adverse events remained constant over time. CONCLUSIONS: At start of etanercept treatment, patients had high disease activity. Activity remained high in a large proportion of the responding patients. Although serious ADRs occurred during late phases of treatment, no unexpected safety problems arose. No specific indicators of ADR risk were found. The monitoring system that was established may be useful in future postmarketing surveillance. (+info)
Lessons from the national cooperative growth study.
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OBJECTIVE: To review the National Cooperative Growth Study (NCGS), a national post-marketing surveillance program for children treated with biosynthetic growth hormone (GH) products from Genentech. METHODS: Representative data are presented to summarize the extensive experience of the NCGS. This study is a multicenter, observational surveillance registry begun in 1985 in coordination with the release of the first recombinant DNA biosynthetic GH. RESULTS: After almost 20 years, data from over 47 000 patients representing 165 000 patient years have been collected. There are over 12 000 active subjects (estimated to be approximately 75% of all current patients treated with a Genentech GH product) at 435 centers, providing extensive efficacy and safety data. The GrowTrak program is a secure, user-friendly database which encourages a high level of participation by the pediatric endocrine community in the USA. Efficacy has been shown in a variety of clinical diagnoses, including isolated (IGHD) and organic growth hormone deficiency (OGHD), idiopathic short stature (ISS), and Turner syndrome. Safety monitoring of this large population has provided reassuring evidence that leukemia (de novo or relapse), extracranial nonleukemic neoplasms and central nervous system (CNS) tumor recurrence are not associated with GH therapy. A small risk of intracranial hypertension and slipped capital femoral epiphyses has been suggested, especially in children with renal disease or Turner syndrome. NCGS substudies have also provided important insights into actual clinical practice. For example, screening for renal, cardiac, or auditory comorbidities in Turner syndrome is often done less than is recommended by national guidelines (NCGS 9). Furthermore, almost 65% of children referred for short stature may be lost to follow-up before an evaluation is completed (NCGS 8). CONCLUSIONS: The NCGS has proven to be a valuable method of monitoring the safety and efficacy of biosynthetic GH. The study has attracted wide physician participation due to the data collection software used and the extensive sharing of the analyses of that data with the providers. (+info)
Device and equipment evaluations.
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Device evaluation, which is an essential skill set for the respiratory therapist, ranges from comparing manufacturer's specifications to comprehensive device testing, either with patients or on the bench. Good device evaluations help guide decisions about device selection, procedure development, and risk and failure analysis. Poor evaluations cost time and money and fail to return value. Manufacturer's specifications alone are poor criteria for device selection, because of how and why those specifications are created and the potential gap between the manufacturer's test methods and the complexity of clinical situations. Proper clinical evaluation of devices with patients requires extensive preparation and resource expenditure, and clinical evaluations may not allow isolating key variables to determine specifics of device performance. In vitro testing, using models to simulate discrete components of device/patient interface, is less expensive and easier to conduct. This article discusses the process of experiment design and model development for device and equipment evaluations. (+info)
Review of zonisamide development in Japan.
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Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan. Identified as an anticonvulsant during exploratory research, zonisamide has since been characterized as having broad-spectrum antiepilepsy and neuroprotective effects. Early clinical studies in Japan demonstrated that zonisamide has a long elimination half-life and is well tolerated; Phase II and III clinical trials established the drug's efficacy and safety for the treatment of partial and generalized seizures. In 1989, zonisamide was approved and marketed in Japan under the trade name of Excegran. Data from postmarketing surveillance studies and clinical observations over 10 years of use have continued to support zonisamide's efficacy and safety, identified its usefulness as monotherapy, and characterized its effectiveness for various seizure types and epilepsy syndromes. (+info)
Clinical efficacy of zonisamide in childhood epilepsy after long-term treatment: a postmarketing, multi-institutional survey.
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Postmarketing data about the effectiveness of zonisamide in childhood epilepsy was collected from 759 children with various forms of epilepsy (ages 3 months-15 years) to compare the long-term efficacy of zonisamide in the treatment of epilepsy in intellectually normal versus intellectually disabled children. The follow-up period was 6 months-3 years; 291 children (245 intellectually normal, 46 intellectually disabled) received zonisamide as monotherapy. The remaining patients received additional antiepilepsy drugs (AEDs); mean numbers of additional AEDs were 1.6 and 2.9 for intellectually normal and intellectually disabled groups, respectively. Effectiveness could not be evaluated in 30 of the 759 patients because of very rare or irregular seizure frequency. In the 729 patients evaluated, 78% of intellectually normal patients and 43% of intellectually disabled patients showed > or =50% reduction in the number of seizures (P < 0.001). Improvement rates seen in the intellectually normal group were almost the same for patients with generalized (82%) and partial (77%) epilepsies, whereas in the intellectually disabled group, the improvement rate was higher for partial (50%) than generalized (36%) epilepsies (P < 0.01). These results are consistent with the known phenomenon that intellectually disabled children are likely to have more intractable seizures than children with normal intelligence. (+info)
Efficacy of zonisamide: our experience.
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The current overview of zonisamide use and effectiveness is based on both a long-term prospective postmarketing survey and current zonisamide use at the Saitama Medical College, Department of Neuropsychiatry. Survey data, which were collected from individual physicians and 23 survey groups throughout Japan, assessed the effectiveness of zonisamide in 1631 patients. Zonisamide was highly effective for treating partial seizures, with 70% of patients reporting improvement. More than half of patients with generalized seizures (58%) and half of patients with myoclonic and atypical absence seizures showed improvement with zonisamide treatment. Among the different epileptic syndromes, zonisamide was highly effective in treating generalized idiopathic epilepsy (> or =78% improvement) and partial epilepsy (> or =58% improvement). However, only 28% of patients with West syndrome or Lennox-Gastaut syndrome showed improvement. Among 60 outpatients treated with zonisamide at our facility as of October 1998, most had partial seizures or generalized seizures subsequent to partial seizures. The majority of patients received zonisamide in combination with other antiepilepsy drugs. Patients receiving zonisamide monotherapy showed greater improvement than did patients receiving polytherapy. We conclude that zonisamide is highly effective for partial seizures and generalized seizures, and that there appears to be no decrease in efficacy with long-term use. (+info)
Safety of zonisamide therapy: prospective follow-up survey.
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Zonisamide safety was evaluated based on a postmarketing surveillance study of patients treated for 1-3 years. Nine hundred twenty-eight children and 584 adults (ages 1 month to 79 years), including 372 newly-diagnosed patients, received zonisamide for partial and generalized epilepsies. Of the intractable patients, 1008 received zonisamide in combination with other antiepileptic drugs (AED), and 52 successfully transitioned to zonisamide monotherapy. A total of 1089 adverse events occurred in 476 (31.5%) of 1512 patients. Incidence of adverse effects was significantly lower among patients receiving zonisamide monotherapy than in those receiving polytherapy: 21% (18.9% of children, 29.4% of adults) versus 35.6% (30.4% of children, 41.7% of adults), respectively. The total incidence of adverse effects was lower for children (26.2%) than for adults (39.9%). Most common adverse events included mental/psychiatric symptoms (19.4%), gastrointestinal symptoms (8.7%), and neurological symptoms (5.8%). Effects that seemed unique to zonisamide were impairment of mental function, motivation or volition, and hypohidrosis. Urinary calculi were detected in only two patients (0.13%). Teratogenicity was evaluated in six patients. Two patients on zonisamide monotherapy and three on polytherapy delivered normal children. One of four patients on polytherapy conceived a fetus with a skull defect with cerebral and cerebellar dysgenesis. (+info)