Med Check

Legal Brief

• The Massachusetts Public Health Council, a division of the state's Department of Public Health, released proposed regulations in December 2008 to restrict the pharmaceutical and medical device industry's gifts and payments to physicians and make these gifts and payments public. At press time, the council had planned to hold public hearings for comments on these proposed regulations.

The proposed regulations would require companies to adopt and adhere to the state's requirements for salespersons who interact with health care professionals, prohibit certain payments to health care providers, and publicly disclose payments valued at $50 or more. These regulations were drafted in accordance with laws passed by the state's legislature and signed by the governor in August 2008.

Regulatory Briefs

• The FDA's Division of Drug Marketing, Advertising, and Communications sent a warning letter to AstraZeneca in December 2008 regarding an illegal marketing practice to promote its drug quetiapine fumarate. The letter alleged that a telephone call made by a company sales representative and follow-up materials mailed to a health care professional made claims that quetiapine is effective in treating major depression. However, the drug has not been approved for this indication, and promoting unapproved indications by the manufacturer is prohibited by law. The agency requested the company to stop disseminating these messages and materials immediately.

The letter is posted at<www.fda.gov/cder/warn/2008/Seroquel_Ltr.pdf>.

• Also in December, the FDA requested that AstraZeneca submit additional data to support the company's application to add major depressive disorder as a new indication for quetiapine fumarate extended-release tablets, according to a company announcement. The drug is currently approved in the U.S. for treatment of schizophrenia and bipolar disorder. AstraZeneca said it would evaluate the request and “provide a response to the agency in due course.”

• An oral-spray formulation of the prescription sleep aid zolpidem tartrate (Zolpimist) was approved by the FDA for short-term treatment of insomnia characterized by difficulty falling asleep, the manufacturer of the product, NovaDel Pharma Inc., announced on December 22, 2008. In two clinical trials, the oral spray was shown to have pharmacokinetic and safety profiles comparable to those for zolpidem oral tablets.

• The Prescription Project, an industry watchdog organization led by the nonprofit Community Catalyst and the Institute on Medicine as a Profession, filed citizen petitions to the FDA on December 3, 2008, urging the agency to exercise its authority to regulate direct-to-consumer (DTC) drug and device advertisements produced as online videos. In addition, the agency was urged to issue a guidance document for the industry to clarify and restrict the content and scope of such advertisements.

The petitions specifically cited promotional videos on YouTube.com (about medical devices manufactured by Abbott Laboratories, Medtronic, and Stryker) for not including all the disclosures and warnings required by current DTC rules for print and broadcast media. The petitions also pointed out that online DTC consumer advertisements are increasingly used by the industry through various Web outlets.

The petitions are posted at<www.prescriptionproject.org/citizen_petition>.

• New warnings and adverse reactions were added to the labeling of the prescript ion sleep aid ramelteon (Rozerem), according to an FDA MedWatch announcement. Patients who experience angioedema from the drug should not be rechallenged. Rare “severe anaphylactic, anaphylactoid reactions” and “abnormal thinking and behavioral changes” such as the worsening of depression, hallucinations, bizarre behavior, and“ sleep-driving” (described as a more complex form of sleepwalking) were added to the “Warnings and Precautions” section.

Detailed labeling changes are posted at<www.fda.gov/medwatch/safety/2008/oct08.htm#Rozerem>.

Industry Briefs

• Schering-Plough announced on November 24, 2008, that the investigational drug asenapine was shown to be significantly more effective than placebo in preventing relapse of schizophrenia in a randomized, double-blind, controlled, phase 3 clinical trial. In the 26 weeks of the trial, 47 percent of the patients taking placebo and 12 percent of those taking asenapine relapsed, a statistically significant difference. The 386 patients enrolled in this trial had previously been stabilized on asenapine for acute treatment of schizophrenia. The company's announcement did not specify the number of patients in each treatment group.

• The long-acting injectable formulation of paliperidone palmitate was shown to be more effective than placebo in treating schizophrenia, according to results of a 13-week, randomized, double-blind, controlled clinical trial conducted by its maker, Johnson and Johnson Pharmaceutical Research and Development. The results were announced on December 10, 2008. The primary outcome of symptom control was assessed with the Positive and Negative Syndrome Scale (PANSS) total score.

Also, in a 53-week randomized trial, flexible-dose paliperidone palmitate injection plus oral placebo was compared with long-acting risperidone injection plus orally supplemented risperidone. The results indicated that both regimens led to reductions in PANSS scores, but the statistical analyses failed to prove that the paliperidone-plus-placebo regimen was at least as effective as the injection-plus-oral risperidone regimen. The company planned to conduct another phase 3 comparative trial of the two drugs using a higher loading dose of paliperidone, according to the announcement.

In both clinical trials, the long-acting injection was given every four weeks.

The oral tablet formulation of paliperidone is available in the United States and Europe for indications of acute and maintenance treatment of schizophrenia.

• An investigational agent known as LX6171, which was being studied for treatment of age-associated memory impairment, failed a phase 2 clinical trial, according to a December 12, 2008, announcement by Lexicon Pharmaceuticals, the company developing the drug. LX6171 is a small molecule that inhibits SLC6A7, a high-affinity L-proline transporter expressed in synaptic vesicles and presynaptic membranes of glutamatergic neurons in the central nervous system. Growing evidence from basic research suggests that the glutamatergic signaling system has a critical role in memory and learning. In the clinical trial, healthy elderly subjects with age-associated memory impairment taking daily LX6171 for four weeks did not perform significantly better in attention or memory tests compared with those taking placebo. Given the disappointing results, the company indicated in the announcement that the drug would be dropped from clinical development.

• A once-promising drug candidate being developed for treating cognitive dysfunction in schizophrenia was dropped by Targacept Inc. and AstraZeneca after disappointing results from a phase 2 clinical trial, the companies announced on December 9, 2008. In the trial of 445 subjects with schizophrenia, the agent known as TC-1734 did not show a significant benefit compared with placebo. The molecule targets the nicotinic receptor in the central nervous system.

• H. Lundbeck A/S announced on December 15, 2008, that the company was initiating three phase 3 clinical trials to develop the investigational drug nalmefene for treatment of alcohol dependence. Nalmefene, formulated as an oral tablet, is an opioid receptor antagonist that potentially reduces cravings for alcohol. ▪