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In The News
Charges of Lax Disclosure Policies, Corruption Leveled at FDA on Eve of Administration Change
The New Year hasn't brought the FDA any headlines of ringing endorsement. A recent report by the HHS Office of the Inspector General says the agency is too relaxed in examining potential conflicts of interests in drug and device trials. For the study, the authors examined 118 applications for newly approved medications from 2007. They discovered that 42 percent of the applications didn't reveal their entire financial information and less than one percent of the researchers included information about potential conflicts of interest.
"We found a number of limitations in FDA's oversight, leaving FDA unable to determine whether (drug companies) submit financial information for all clinical investigators." The authors said that such limitations "could result in FDA being unaware of a clinical investigator's financial interest, and thus unable to gauge its potential bias on clinical trial results."
The one percent of applicants who disclosed a potential conflict of interest almost unanimously disclosed only one financial interest. Investigators also say that in 31 percent of the applications that included required disclosures, the FDA didn't specify that the agency had examined the information. Of the applications in which disclosures were made of significant financial conflicts, reviewers from FDA and the sponsoring companies did not do anything to address the conflicts in 20 percent of cases, the study found.
The rules of disclosures can be potentially skirted because of an exemption that allows companies to withhold financial conflict disclosures if they can show that their attempts to collect such information from physicians were fruitless.
Karen Riley, a spokesperson for FDA, said the agency disagreed with the report's recommendation to review physicians' financial conflicts ahead of patient trial because they are only one possible source of bias. The effort to collect and examine the information was not beneficial to the agency or the companies involved, according to the agency, as reported by the New York Times (1/12).
Another setback for the agency came within. In an uncharacteristically blunt letter, a group of federal scientists protested the level of "corruption" at the FDA to the incoming Obama administration. "The purpose of this letter is to inform you that the scientific review process for medical devices at the FDA has been corrupted and distorted by current FDA managers, thereby placing the American people at risk," said the letter, dated January 7 and written on the agency's Center for Devices and Radiological Health letterhead, according to the Associated Press.
The letter, provided to the AP with the scientists' names redacted by a Congressional official, says, "Managers with incompatible, discordant and irrelevant scientific and clinical expertise in devices...have ignored serious safety and effectiveness concerns of FDA experts. Managers have ordered, intimidated and coerced FDA experts to modify scientific evaluations, conclusions and recommendations in violation of the laws, rules and regulations, and to accept clinical and technical data that is not scientifically valid."
An FDA spokesperson told the AP says they are working with the scientists to address their concerns.
Antipsychotics and AD Don't Mix, Increase Risk of Death
Patients who suffer from Alzheimer's Disease and receive antipsychotics have a higher risk of death than their comparable cohorts who are not given these medications, according to a new study published online in The Lancet Neurology. Using the drugs for a short period can provide modest benefits for some patients but can cause side effects like sedation, chest infections, decline in brain function, stroke, and Parkinson-like symptoms.
Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months.
For their placebo-controlled, parallel, two-group treatment discontinuation trial, researchers had 165 patients randomized (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78 percent) started treatment (64 continued with their treatment and 64 received placebo). A reduction was seen in the survival of patients who continued to receive antipsychotics compared with those who received placebo. The cumulative probability of survival throughout the 12 months was 70 percent (95% CI 58-80%) in the continue treatment group against 77 percent (64-85%) in the placebo group for the mITT population.
The study authors say, "Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02)." They found the hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. "The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival: 46 percent versus 71 percent; 36-month survival: 30 percent versus 59 percent)," they write.
Psychosis of AD is characterized by delusions or hallucinations and may be associated with agitation, negative symptoms or depression.1 There are no psychotropic medications that are approved by the FDA for the treatment of psychosis of AD.
FDA Actions
FDA Approves More Drugs in '08. The Food and Drug Administration gave the thumbs up to 24 new drugs in 2008, more than any of the previous three years, according to the Wall Street Journal. The agency approved 18 drugs in 2007, 22 in 2006, and 20 in 2005. According to the Journal, the agency's high 2008 approval rate is "a consolation of sorts to an industry struggling with greater scrutiny, thousands of layoffs and thinning drug pipelines." Despite the higher number of green lights, delays in the approval process were more notable in 2008. The FDA resolves to reach a final decision on 90 percent of applications within the six- to 10-month time frame. However, the agency says it missed 32 out of 159 drug application deadlines, or 20 percent, through October 31, 2008.
Short Takes
Stimulating Parkinson's. Deep brain stimulation was more effective than the "best medical therapy" in improving on time without troubling dyskinesias, motor function, and quality of life at six months, in a significant new study (JAMA. 2009;301(1):63-73) but was associated with an increased risk of serious adverse events. The randomized, multicenter, controlled trial enrolled 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications). Of particular note, 25 percent of the patients were 70 or older, a population unrepresented in previous trials. These patients received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) between May 2002 and October 2005.
Patients who received DBS added a mean of 4.6 hours per day of on time without troubling dyskinesia compared with 0 hours per day for patients who received best medical therapy. Motor function improved significantly (P< .001) with DBS versus best medical therapy, to the point that 71 percent of DBS patients and 32 percent of best medical therapy patients experienced clinically meaningful motor function improvements. At least one serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients.
For another component of the study, DBS was targeted to subthalamic nucleus or to the globus pallidus. Those results have not been released.
This is Spinal Cost. With a price tag of more than $100 billion, an obvious question emerges: Is spinal surgery worth it? A study published in the December 16th issue of the Annals of Internal Medicine came back with a mixed bag. For patients with spinal stenosis, a laminectomy, or surgical removal of some soft bone and tissue, it's a practical value. Unfortunately, for patients suffering from spinal stenosis with associated slipped vertebrae, the payback of spinal fusion surgery may not be enough to atone for the costs.
Researchers used the Quality Adjusted Life Year (QALY) scale to weigh the benefit to patients in comparison to direct and indirect costs of the surgical procedures over a two-year time following surgery. More than 3,900 patients participated in the randomized, controlled trial of surgery versus non-operative treatment, including 320 who underwent laminectomy and 344 who had spinal fusion. The researchers say that stenosis surgery using laminectomy cost $77,000 per QALY gained. In comparison, spinal fusion surgery for stenosis with slipped vertebrae cost about $115,000 for each QALY gained. $100,000 is the threshold at which procedures are considered to be cost effective in the US.
Botulism Toxin Structure E-xposed. Scientists at the US Department of Energy's Brookhaven National Laboratory say they have uncovered the atomic-level structure of a third subtype of botulinum neurotoxin, according to new research published online December 22, by the Journal of Molecular Biology. Previously, the group analyzed the molecular-level structures of various fragments of botulinum neurotoxin subtypes A to F, believing that in subtypes A and B, the three domains were set in identical fashion: with the binding and protein-cleaving domains "flanking" the translocation domain, indispensable for shifting the toxin into the cell.
Instead, the researchers say, the binding and protein-cleaving domains of subtype E both exist on the same side of the translocation domain. In addition, while all other subtypes are made of two protein chains, subtype E is a single-chain molecule. The scientists hope this will allow faster-acting vaccines and therapeutic agents to be developed more quickly.
Old News. Antidepressants in PD. Older antidepressants may not be the best choice for depression in patients with Parkinson's, according to a study published in the December 17th online edition of Neurology. For the study, researchers gave 52 people diagnosed with PD and depression either nortriptyline, a tricyclic antidepressant, paroxetine CR, a selective serotonin reuptake inhibitor (SSRI) or a placebo pill. The patients were tested for improvement of depression symptoms at two, four and eight weeks after starting treatment. Those who took nortriptyline were nearly five times more likely to see improvement in depression symptoms when compared with the people who took paroxetine CR, the study found.
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