Recently in FDA Category
While the FDA considers whether to add suicide warnings to the labels of 11 epilepsy drugs,* the measure is unlikely to affect prescriptions—at least by neurologists. That's because the cost of nonadherence to anticonvulsant therapy among epileptic patients is known to be so high.
For example, in this week's print issue of Neurology, investigators report a 3-fold increased risk of death among nonadherent epileptic patients in a retrospective study of Medicaid claims from Florida, Iowa, and New Jersey (N = 33,658).** Nonadherence, determined by non-possession of medication, was also associated with significantly more ER visits (50% increased risk), hospital admissions (86%), car accidents (108%), and bone fractures (21%).
In the FDA's assessment of 199 placebo-controlled studies of patients with epilepsy, selected psychiatric illnesses, or pain conditions (N = 43,892), there were only 4 (0.009%) suicides in drug-treated patients and none in placebo-treated individuals. Suicidal behavior or ideation was reported in 0.37% of patients who received an anticonvulsant and in 0.22% of those who received placebo. While the risk of suicidality is almost 70% higher with anticonvulsant treatment, the absolute risk remains small at 0.15%. Not surprising, the risk of suicidality with either drug treatment or placebo was lower in epileptic patients than in psychiatric patients (see table).
|
Indication |
Suicidality Risk, % |
Relative Risk Increase, % |
Absolute Risk Increase, % | |
|
Placebo |
Drug | |||
|
Epilepsy |
0.10 |
0.34 |
240 |
0.24 |
|
Psychiatric |
0.57 |
0.85 |
49 |
0.28 |
|
Other |
0.10 |
0.18 |
80 |
0.08 |
|
Total |
0.22 |
0.37 |
68 |
0.15 |
The FDA is holding a public advisory meeting on the risk of suicide with anticonvulsant drugs on July 10.
Photo: iStockPhoto.
*The 11 drugs are carbamazepine (Carbatrol; Shire); felbamate (Felbatol; Meda); gabapentin (Neurontin; Pfizer), lamotrigine (Lamictal; GSK); levetiracetam (Keppra; UCB); oxcarbazepine (Trileptal; Novartis); pregabaline (Lyrica; Pfizer); tiagabine (Gabitril; Cephalon); topiramate (Topamax; Ortho-McNeil); valproate (Depakote; Abbott); and zonisamide (Zonegran; Eisai).
**The study was sponsored by GSK, maker of Lamictal (lamotrigine). One of the study authors is an employee of GSK, and the other authors report support from GSK, in the form of research grants and/or "other activities."
In an ongoing effort to protect consumers from fraudulent cancer treatments, the FDA sent warning letters to 25 web-based businesses from April 17 to June 9. The warned companies or entities and a list of their 125 "fake cancer 'cure' products" were posted yesterday at the FDA web site. These letters follow a series of warning letters sent by the FTC earlier this year to 112 web sites, which falsely promoted cancer treatments, says the FDA. Consumer complaints and a web search performed by the FDA, FTC, and members of the Mexico-US-Canada Health Fraud Working Group prompted the overdue crackdown.
At least 3 of the targeted entities are already known to the FDA. A search of warning letters at Casewatch indicates that Vitasalus Inc (Nu-Gen Nutrition), Vitapurity, and H&L Worldwide all received earlier letters from the FDA, which claimed that the businesses promoted products for the "cure, mitigation, treatment, or prevention of diseases" in violation of the Federal Food, Drug, and Cosmetic Act. These repeat warnings do not necessarily include the numerous instances in which companies have fraudulently hawked the same products—for example, "Coral Calcium" or "Curcumin"—in rotating fashion as disease treatments.
An FDA warning letter sent to Vitasalus (Nu-Gen Nutrition) in May 2002 cited a single website, cancerchoices.com, and the product Squalamax. However, the most recent FDA letter cites 7 websites and 6 other products, in addition to Squalamax. A Wayback search reveals that 6 of the 7 Vitasalus websites named this year existed in 2002. The 2 other companies, H&L Worldwide (Chang Li) and Vitapurity (Otto Roder), have evidently not moved their cyber or land-based addresses since the time of their FDA warning letters in 2004 and 2005, respectively. Given the number of products promoted by each company and those cited by the FDA this year, business does not seem to have suffered for either company in the interim.
Leaders of the Energy and Commerce committee, John Dingell (D-MI) and Bart Stupak (D-MI), requested that 4 drug companies adhere to rules for direct-to-consumer (DTC) ads that are mostly already in place. The letters were sent May 20 to leaders at JNJ, Pfizer, Merck, and Schering-Plough following a May 8 congressional hearing, "Direct-to-Consumer Advertising: Marketing, Education, or Deception?" Responses to the representatives' letters were posted yesterday at the committee's website.
Today's media coverage largely focuses on the representatives' request for a voluntary, 2-year moratorium on DTC advertising of new drug products, which was declined by the companies. However, Dingell and Stupak made other requests, as described in sequence here:
- That the companies follow the AMA's guidelines for the use of actors and health professionals in DTC ads.
The AMA's policy H-105.988 states that "product-specific DTC advertisements should not use an actor to portray a health care professional...because this portrayal may be misleading and deceptive. If actors portray health care professionals in DTC advertisements, a disclaimer should be prominently displayed." Also "[t]he use of actual health care professionals, either practicing or retired, in DTC to endorse a specific drug or implantable medical device product is discouraged but if utilized, the advertisement must include a clearly visible disclaimer that the health care professional is compensated for endorsement."
The representatives' request is, no doubt, a response to Pfizer's semi-controversial use of artificial-heart inventor Robert Jarvik to promote Lipitor in its now-pulled DTC ads. Pfizer replied to the committee that it is "currently working internally to ensure that the recent AMA guidelines...are fully incorporated into our DTC advertising when applicable." Merck responded that none of its current DTC ads use physicians or actors who play physicians. All companies, including JNJ and Schering-Plough, agreed to comply with the AMA policy in cases where it might be relevant.
2. That DTC ads not market products until a "valid outcomes study" is completed, and the results are released.
The representatives' definition of valid outcomes is not entirely clear; although they may be referring to longer-term clinical outcomes—for example, cardiac events instead of surrogate cholesterol levels in the case of cholesterol-lowering medications (ie, statins). Certainly DTC ads can only promote the use of FDA-approved pharmaceuticals, which must show at least clinically meaningful efficacy and safety to be approved. JNJ wrote that it has concerns about categorically prohibiting DTC ads "before completion of studies of an undetermined time and nature." Merck indicated that it would defer to the FDA on this point. Pfizer and Schering-Plough (which market Lipitor and Vytorin, respectively) indicated that waiting for long-term clinical outcomes would compromise consumer education and, therefore, consumer health.
3. As recommended by the Institute of Medicine, that there be a 2-year (instead of the conventional 6-month) moratorium on DTC ads for new prescription drug products.
In 2006, the IOM recommended that the FDA require a special product label to identify a new drug or new drug combination, and that DTC advertising should be restricted during 2 years. The FDA has not implemented the IOM's recommendation. All companies contacted by the representatives indicated that they abide by a general, internal 6-month moratorium on DTC advertising and would continue to do so. The companies cite PhRMA guidelines, which state that "companies should spend an appropriate amount of time to educate health professionals...before commencing the first DTC advertising campaign...[C]ompanies should take into account the relative importance of informing patients of the availability of a new medicine, the complexity of the risk-benefit profile of that new medicine and health care professionals' knowledge of the condition being treated."
4. That DTC drug ads should not market off-label uses.
Probably the most blatant example of grandstanding by the congressmen. Of course, DTC advertising must comply with FDA-approved labeling, and all companies indicated their compliance.
5. That DTC ads include the FDA's toll-free MedWatch phone number for reporting adverse events.
Current law mandates the listing of the MedWatch number in DTC print ads, and a toll-free information number in televised ads. JNJ indicated that it would include the MedWatch number in its TV ads. The other companies stated that they would defer to the FDA, pending the agency's ongoing investigation of this particular matter.
6. That so-called black-box warnings be included in DTC ads.
Merck and Schering-Plough indicated that they did not have any DTC ads for products with black-box warnings, and all companies replied that they have deferred (ie, Pfizer) or would defer to the FDA about how to incorporate such safety information into DTC ads.
HT for story: Pharmalot.
Progress in the study of stem cells for neurologic conditions is outpacing ethical oversight in the United States, according to a multiauthored "review-itorial" in last week's online version of Neurology. At least 6 stem-cell products are currently under investigation for neurologic disorders (tabulated below), one of which is in phase 1 development, despite the fact that no review is required at the national level for their study.* Like any other human clinical trial, the study of stem cells is currently relegated to institutional review boards (IRBs) and the FDA, in addition to local embryonic stem-cell research oversight committees (ESCROs).
|
Condition |
Status |
Stem Cell Line |
Sponsor |
|
Batten disease (infantile or late infantile neuronal ceroid lipofuscinosis) |
Phase 1 |
HuCNS-SC (human fetal brain) |
StemCells (study location: Oregon Health and |
|
Post-stroke |
Preclinical |
MultiStem (adult bone marrow) |
|
|
Post-stroke |
Preclinical |
NurOwn (human autologous bone marrow–derived neural-like cells) |
|
|
Spinal cord injury |
Preclinical |
GRNOPC1 (human oligodendrocytes and dopaminergic neurons) |
|
|
Post-stroke, Huntington's disease |
Preclinical |
NtCell (porcine choroid plexus) |
|
|
Post-stroke |
Preclinical |
ReN001 |
The authors acknowledge that many of the ethical issues raised by the clinical study of stem cells are similar to those in any clinical endeavor; however, there are ethical challenges which are specific to something as novel as stem-cell clinical trials, particularly when they involve the central nervous system. These include heightened risks related to the development of abnormal brain function, which may be difficult to discern and the timing of which is unclear, and the possible transmission of genetic disease (which is not necessarily peculiar to the stem-cell treatment of neurologic conditions).
*National review of stem-cell study is, for instance, required in the UK by the Human Fertilisation and Embryology Authority.
Chinese health officials continue to claim that the artificial contaminant, oversulfated chondroitin sulfate, in lots of Baxter's recalled heparin was not the cause of the 81 associated deaths and hundreds of allergic reactions that occurred in the United States, reports Reuters. The Chinese assertion comes in the wake of reports in the NEJM and Nature Biotechnology, which described the contaminant as structurally identical to a withdrawn intramuscular drug, Arteparon, and the contaminant's actions on the kinin-kallekrein pathway.
The Chinese food and drug agency points to the fact that only patients in the United States or Germany experienced adverse reactions to the tainted heparin, whereas the contaminant has been found in heparin products in other countries. The Chinese agency also claims that adverse reactions have occurred with some batches that did not contain the contaminant. Both of these assertions, however, have already been rebutted by the US FDA, which cited the relatively common practice of heparin bolusing in the United States and Germany and the initial use of an insufficiently sensitive test for the heparin contaminant.
In what appears to be a digressive move, Chinese officials accuse Baxter of obstructing their investigation of the company's tainted heparin, a charge that Baxter denies. A Chinese regulator is quoted by Reuters: "Baxter failed to provide necessary cooperation in the process of the investigation, which is not conducive to further identifying the reasons for the adverse reactions to heparin." Baxter is also accused of destroying some drug samples and relevant production records—an allegation also denied by the company. Chinese officials also point a finger at Baxter's Chinese heparin supplier Changzhou SPL, implying that the company avoided registration with China's food and drug administration because the company was considered a chemical manufacturer, not a drug maker.
Most important, however, Chinese health officials have yet to explain how the artificial contaminant made its way into heparin. Information to date suggests that the contaminant, which is considerably cheaper than crude heparin, was intentionally introduced into supplies at the workshop level, before processing at Changzhou SPL.
The US Food and Drug Administration wants to hire more than 1300 people during fiscal year 2008, according to today's press release. That's nearly 3 times the number of people who were hired during the previous 3 years, reports the agency.
Critically needed are medical and science professionals to fill new and existing positions throughout the FDA's various divisions to implement the FDA Amendments Act of 2007, the Food Protection Plan, and the Import Safety Action Plan. The FDA also writes that qualified candidates could be on the job in as little as 3 weeks at any number of locations, including in the DC headquarters area, across the country, or overseas.
FDA job fairs will begin mid-May and continue through September at various conferences throughout the country, including those in DC, Dallas, Boston, Denver, Seattle, San Diego, New Orleans, Columbus (OH), and Philadelphia. An overseas job fair in May will be held in Bonn, Germany. The FDA also makes it easy to apply online by submitting a CV and cover letter to JOINOURTEAM@FDA.GOV. Good luck.
The contaminant identified in recalled lots of heparin, an oversulfated chrondroitin sulfate with a tetrasulfated disaccharide repeat, has not been isolated to date from animal tissues, according to data published online yesterday in Nature Biotechnology. Investigators suggest that the contaminant was, therefore, intentionally introduced into the product.
Other important information from the article:
- Synthetic tetrasulfated disaccaride repeat units of chondroitin sulfate exhibit antithrombin activity, which probably explains how the contaminated heparin passed an activity screen, such as a whole-blood coagulation test.
- The contaminant is structurally identical to Arteparon,* an intramuscular drug that was marketed in Europe for the treatment of individuals with degenerative joint disease. Arteparon has been shown to induce an allergic-type response and was withdrawn from the market because of patient deaths, most likely due to thromboembolic complications.
*As far as I can tell, Arteparon is identical to Adequon, which is marketed by Novartis for canine arthritis and by Luitpold for equine joint disease.
The contaminant in recalled heparin lots appears to trigger hypotension and other adverse reactions by activating the kinin-kallikrein pathway and generating anaphylactoid complement proteins. Testing of the isolated contaminant, oversulfated chondroitin sulfate, and a synthetically generated version on human plasma and in pigs was reported in today's NEJM.
Among the most intriguing findings was the fact that not all animals treated with the contaminated heparin developed adverse clinical signs; however, all treated animals demonstrated activation of kallikrein. On the basis of this observation, the authors speculate that some patients who received the tainted heparin, such as those undergoing dialysis, may have been more vulnerable to the contaminant's contact-system-induced hypotensive effects, because of concurrent exposure to the dialysis membrane (which also activates the contact system) or treatment with ACE inhibitors (which block bradykinin degradation).
The authors conclude that a simple in vitro bioassay that assesses kallikrein activity, in addition to more sophisticated analytic tests, will aid the screening of heparin lots for oversulfated chondroitin sulfate and other polysulfated contaminants.*
*Dermatan sulfate, a known heparin impurity, was found in most of the contaminated lots; however, the compound's presence was not associated with kallikrein activity.
According to the AP, the FDA said yesterday that there is a "solid link" between the hundreds of allergic reactions and now 81 deaths associated with Baxter's recalled heparin and a contaminant, identified as oversulfated chondroitin sulfate. The FDA statement is a response to a Chinese official's claim that the contaminant could not be the source of the adverse reactions, because some batches of the implicated heparin did not contain it. The FDA also responded that this claim is based on false assumptions.
Baxter's heparin supplier, Wisconsin-based Scientific Protein Labs, said in related news, "It is now clear that the suspect contaminant was introduced earlier in the supply chain in China and was widespread throughout the unrelated Chinese supply chains of many companies." SPL owns a Changzhou plant, which buys its crude material from Chinese heparin "workshops." The plant was cited by the FDA in February for a number of "significant deviations" from good manufacturing processes.
The FDA publicly released its warning letter to SPL's Changzhou facility yesterday, which included the following admonishments:
- There is no assurance that processing steps used to manufacture heparin sodium, USP are capable of effectively removing impurities.
- You fail to have adequate systems for evaluating the suppliers of heparin crude materials, and the crude materials, themselves, to ensure that these materials are acceptable for use.
- Equipment used to manufacture heparin sodium USP is unsuitable for its intended use.
Forehead-slapping insights like these explain why Andrew von Eschenbach's head of the FDA and you're not.
