Forest Laboratories Research Articles

FDA Catching Up With Drug Companies That Push Online Envelope

Back to table of contents Previous article Next article Professional NewsFull AccessFDA Catching Up With Drug Companies That Push Online EnvelopeJun YanJun YanSearch for more papers by this authorPublished Online:5 Jun 2009https://doi.org/10.1176/pn.44.11.0004aFourteen pharmaceutical companies have received warning letters from the Food and Drug Administration (FDA) about violating direct-to-consumer (DTC) advertisement regulations in their paid links on Internet search engines.In recent years the pharmaceutical and medical-device industries have been aggressively expanding marketing campaigns into online media. The FDA has had to step up its monitoring and regulatory actions in response (Psychiatric News, March 20).Sent on April 2, the most recent batch of warning letters from the agency's Division of Drug Marketing, Advertising, and Communications targeted a number of major pharmaceutical companies over dozens of prescription drugs they were advertising online. The agency's objections focused on sponsored links and accompanying short statements posted on Google that were intended to attract Internet users to visit promotional Web sites for the products (see screenshot). Several drugs named in these warning letters are often prescribed in psychiatry, including Forest Laboratories' acamprosate, escitalopram, and memantine; Pfizer's pregabalin; Boehringer Ingelheim's pramipaxole; and Eli Lilly's duloxetine.Eli Lilly, for example, was criticized for suggesting the efficacy of duloxetine in the online blurb “Learn about an SNRI for depression called Cymbalta® (duloxetine HCl),” along with a link to the product's Web site, without giving any information about potential adverse events and safety risks. Forest Laboratories' links for several drugs, including memantine, donepezil, and escitalopram, “inadequately communicate[d] the drugs' indications ... and fail[ed] to use the required” generic names.The other warning letters cited similar problems with not including adequate information about safety risks and complete indications.The use of “sponsored links” that are posted on the pages of Internet search engines has become a popular marketing strategy for companies and organizations to promote their Web sites and products. It is inexpensive and has the advantage of targeting advertisements to people who are already looking for information about a particular product or related subjects such as disease information.However, these sponsored links are given limited space (95 characters by Google) for a statement to accompany the link. The FDA's warning letters have made it clear that the agency is sticking to its rules for all public-access pharmaceutical promotional materials and requires a complete and balanced representation of both efficacy and safety information when a specific product is advertised. Web sites' length limit for sponsored links is likely to make it impossible for companies to go much beyond stating drug names.As have other companies in other industries, pharmaceutical and medical-device manufacturers have been testing various ways to expand their online marketing presence. In addition to YouTube video postings and channels, companies are making more use of online social networks such as Facebook and MySpace to connect with consumers directly. For example, McNeil Pediatrics, a division of Johnson & Johnson, has launched Facebook pages, or“ online communities,” for adults with attention-deficit/hyperactivity disorder (ADHD) and for mothers of children with ADHD. McNeil's ADHD drug methylphenidate hydrochloride extended-release tablets (Concerta) won FDA approval for treating adults in June 2008.The FDA warning letters to pharmaceutical companies are posted at<www.fda.gov/cder/warn/warn2009.htm>.▪ ISSUES NewArchived

Psychiatric Treatment Received by Primary Care Patients With Panic Disorder With and Without Agoraphobia

Psychiatric Treatment Received by Primary Care Patients With Panic Disorder With and Without Agoraphobia

Prevalence of and Gender Differences in Psychiatric Disorders Among Juvenile Delinquents Incarcerated for Nine Months

Prevalence of and Gender Differences in Psychiatric Disorders Among Juvenile Delinquents Incarcerated for Nine Months

Med Check

Med Check

Antidepressant Marketing Tactics Lead to Federal Lawsuit

Antidepressant Marketing Tactics Lead to Federal Lawsuit

A pooled analysis of two randomized, double-blind, placebo-controlled trials of milnacipran monotherapy in the treatment of fibromyalgia

Effective fibromyalgia (FM) treatment requires identification of well-tolerated medications that improve pain and other associated FM symptoms. In 2 randomized, placebo-controlled trials, milnacipran improved multiple FM symptoms and was safe and well-tolerated. To validate these findings, a post hoc analysis of pooled data from these studies was conducted. Both trials were similar in patient selection, study design, and efficacy assessments. Patients received placebo (n = 624), milnacipran 100 mg/day (n = 623), or milnacipran 200 mg/day (n = 837). Two composite responder definitions were used to classify each patient's individual response to therapy. FM responders (overall responders) concurrently satisfied response criteria for clinically meaningful improvements of pain (≥30% improvement from baseline in VAS 24-hour recall pain scores), Patient Global Impression of Change (PGIC, rating of “very much improved” or “much improved”), and physical functioning (≥6-point improvement from baseline in SF-36 PCS scores). FM pain composite responders concurrently satisfied response criteria for clinically meaningful improvements in pain and PGIC. Pooled results at 15 weeks were analyzed by linear mixed-effect models. The percentage of patients who were overall responders was significantly greater in each milnacipran treatment group (23.6%, 200 mg/day; 21.1%, 100 mg/day) compared to placebo (9.6%) (each dose vs placebo, P < .001). Likewise, a significantly greater proportion of milnacipran-treated patients were considered FM pain composite responders (42.8%, 200 mg/day; 36.8%, 100 mg/day) compared to placebo (20.6%) (each dose vs placebo, P < .001). Analysis of individual outcomes indicated significant improvements from baseline with each milnacipran dose compared to placebo in pain (P < .05), global status (P < .001), physical functioning (P < .01), and fatigue (Multidimensional Fatigue Inventory, MFI) (P < .05) at 15 weeks; cognition (Multiple Ability Self-report Questionnaire, MASQ) significantly improved with milnacipran 200 mg/day (P < .01). These results further support the conclusion that milnacipran is effective for the treatment of FM and its associated symptoms. (Supported by Forest Laboratories, Inc. and Cypress Bioscience, Inc.)

Milnacipran improves health-related quality of life in patients with fibromyalgia (FM): results from a pivotal phase III randomized controlled trial

Fibromyalgia (FM) is associated with multiple impairments. A pivotal milnacipran clinical trial was analyzed for impact on SF-36 domains. Patients received milnacipran 100 mg/day, 200 mg/day, or placebo for 15 weeks (N = 1196). Health-related quality of life (HRQOL) improvements were evaluated using SF-36 Physical Component Summary (PCS), Mental Component Summary (MCS), and individual domain scores at each visit. Baseline PCS scores were found to be approximately 2 standard deviations (SDs) lower than age- and gender-matched US norms (17.6-18.1 point decrements). Baseline MCS scores reflected less impairment (7.1-9.3 point decrements; within 1 SD of norms). Individual domain scores with the greatest baseline impairments were vitality, bodily pain, role physical, and physical functioning. At endpoint, all groups achieved clinically meaningful improvements (≥MCID of 2.5-5.0 points) in PCS scores, with values approaching 1 SD of norms. Least square mean improvements in PCS scores at Week 15 were observed in 100 and 200 mg/day milnacipran-treated patients vs placebo (5.14 and 4.46 vs 3.28, respectively), with significant improvement observed with 100 mg/day (P < .01). Significant improvements >MCID of 5-10 points were evident in physical functioning and bodily pain in milnacipran-treated patients versus placebo (100 mg/day, P < .001; 200 mg/day, P < .01). Endpoint MCS scores approached norms of 50: 46.9 (milnacipran 100 mg/day) and 47.3 (milnacipran 200 mg/day) vs 46.1 (placebo), with significantly greater improvements in patients treated with milnacipran 200 mg/day (P < .05 vs placebo). Endpoint improvements greater than the MCID and significantly greater than placebo were evident with milnacipran 200 mg/day in role emotional (P < .05) and mental health (P < .05) domains; vitality domain scores were significantly improved with milnacipran 100 mg/day versus placebo (P < .01). Treatment with milnacipran resulted in SF-36 domain and MCS scores which approached age- and gender-matched US norms, despite large and clinically significant decrements at baseline. (Supported by Forest Laboratories, Inc. and Cypress Bioscience, Inc.)

Med Check

Med Check

Journal Digest

Journal Digest

Swallow the Medicine

Even easier is for the patient to swallow a dropperfull (0.5 ml) of Infacol® (Forest Laboratories UK Ltd, Bexley, Kent, UK) in 10 ml water prior to the procedure – a practice that I employ routinely prior to diagnostic endoscopy to avoid bubbling of the duodeno-antral bile reflux that may otherwise impair thorough mucosal inspection. It is cheap and (when patients are told that it is infant gripewater and the strawberries before the local anaesthetic banana) it is cheerful!

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study

Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. PAION Deutschland GmbH; Forest Laboratories.

Treatment of Mild-to-Moderate Acute Pain: What Can We Do to Improve the Standard of Care?

Kaiser Permanente Escondido, CA University of California School of Medicine San Diego, CA Dr. McCarberg reports serving on the speakers' bureau for Abbott Laboratories, Alpharma Inc, Cephalon, Eli Lilly and Company, Endo Pharmaceuticals, Forest Laboratories, King, Ligand, Merck and Co, Inc, Mylan Inc, Pfizer Inc, Pricara, and Purdue Pharma LP.

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry

Clinical topics in cystic fibrosis

This supplement arises out of the 21st one-day meeting on cystic fibrosis (CF) organized by the Section of Paediatrics of the Royal Society of Medicine. The proceedings of the first twenty meetings, held between 1985 and 2006, were published as Supplements to the JRSM, and can still be obtained from RSM Press.1–20 This supplement is also available at www.jrsm.rsmjournals.com. This most recent meeting, organized by Dr Ian Balfour-Lynn, was held at the Royal Society of Medicine in London on 20 November 2007. We are grateful to Forest Laboratories Europe for their support. As in the past, the programme was designed to cover topical practical issues that face those who care for children and adults with CF. The audience comprised a mixture of paediatricians, adult chest physicians, physiotherapists, dietitians, CF specialist nurses, pharmacists and community and primary care medical staff, reflecting the multi-disciplinary approach to the modern management of CF. Topics covered included newborn screening (Diane Asplin), highlights from the 2007 North American CF Conference (Di Bilton), unusual respiratory organisms (Stuart Elborn), adolescence (Terry Segal), selected CF papers published in 2007 (Ian Balfour-Lynn), a debate about the value of segregation (Steve Conway in favour, Duncan Geddes against) and four presentations by trainees. It is hoped that all these papers will be of immediate practical interest to all doctors who care for patients with CF. The next RSM CF meeting will be held on 11 November 2008.

(160) Hypersensitivity to cutaneous thermal nociceptive stimuli in myofascial pain and fibromyalgia syndromes

Traditional paper-based visual analogue scale (VAS) measures used in clinical trials may not sufficiently capture the experience of pain in fibromyalgia (FM). More frequent, real-time, home-based assessments are possible with electronic pain diaries (e-diaries). This study directly compared the performance of e-diaries and paper-based assessments of pain intensity over a 3-month period in the context of a large randomized clinical trial of milnacipran, a potential treatment for FM. FM patients (n 881) were randomized to placebo (n 294), 100 (n 264), or 200 mg/day (n 260) of milnacipran. Pain ratings were collected monthly during clinic visits using traditional paper measures (10-cm VAS) as average pain over the last week or over the previous 24 hours. Daily e-diary monitoring captured pain assessments at semi-random prompts 3-5 times daily; a morning recall of average pain for the previous 24 hours; and average pain over the last week (collected once per week). Paperbased methods produced consistently higher baseline values than did e-diaries; but all 5 measures showed greater agreement at 3-months. Baseline correlations ranged between r 0.60–0.94; whereas 3-month correlations ranged more narrowly r 0.85-0.98. Effect sizes (Cohen’s d) for change in pain at 3 months relative to baseline were calculated comparing each treatment arm to placebo. For milnacipran 100 mg/day, all 5 methods produced comparable effect sizes. For milnacipran 200 mg/day, each of the e-diary methods demonstrated larger effect sizes compared to the paper-based methods. Given the larger effect sizes, e-diary methods appeared to be more sensitive for detecting change over time than paper methods. Enhanced e-diary sensitivity is likely due to decreased dependence upon long recall intervals, denser data collection, and the ability to capture data in patients’ home environment. These data found no superiority of paper over e-diaries, and some advantage of e-diary methodology in terms of sensitivity. Supported by Forest Laboratories and Cypress Bioscience. (162) Pain modulation in IBS and MPS patients: Deficiency of Diffuse Noxious Inhibitory Controls

(161) A comparison between electronic diaries and paper-based pain assessment in individuals with fibromyalgia

Traditional paper-based visual analogue scale (VAS) measures used in clinical trials may not sufficiently capture the experience of pain in fibromyalgia (FM). More frequent, real-time, home-based assessments are possible with electronic pain diaries (e-diaries). This study directly compared the performance of e-diaries and paper-based assessments of pain intensity over a 3-month period in the context of a large randomized clinical trial of milnacipran, a potential treatment for FM. FM patients (n=881) were randomized to placebo (n=294), 100 (n=264), or 200 mg/day (n=260) of milnacipran. Pain ratings were collected monthly during clinic visits using traditional paper measures (10-cm VAS) as average pain over the last week or over the previous 24 hours. Daily e-diary monitoring captured pain assessments at semi-random prompts 3-5 times daily; a morning recall of average pain for the previous 24 hours; and average pain over the last week (collected once per week). Paper-based methods produced consistently higher baseline values than did e-diaries; but all 5 measures showed greater agreement at 3-months. Baseline correlations ranged between r=0.60–0.94; whereas 3-month correlations ranged more narrowly r=0.85-0.98. Effect sizes (Cohen’s d) for change in pain at 3 months relative to baseline were calculated comparing each treatment arm to placebo. For milnacipran 100 mg/day, all 5 methods produced comparable effect sizes. For milnacipran 200 mg/day, each of the e-diary methods demonstrated larger effect sizes compared to the paper-based methods. Given the larger effect sizes, e-diary methods appeared to be more sensitive for detecting change over time than paper methods. Enhanced e-diary sensitivity is likely due to decreased dependence upon long recall intervals, denser data collection, and the ability to capture data in patients’ home environment. These data found no superiority of paper over e-diaries, and some advantage of e-diary methodology in terms of sensitivity. Supported by Forest Laboratories and Cypress Bioscience.

The Role of Corticotropin-releasing Factor in the Pathophysiology of Depression: Implications for Antidepressant Mechanisms of Action

&lt;p&gt;Current antidepressant drugs were developed largely based on two serendipitous findings; first, that monoamine depletion with the antihypertensive agent reserpine causes depression in some patients, and second, that the antitubercular agent isoniazid, which inhibits monoamine oxidase, the enzyme responsible for degrading monoamines extracellularly, was noted to improve patients’ mood. Currently available antidepressants act by blocking presynaptic monoamine transporter proteins, inhibiting monoamine oxidase, and/or by differential actions at pre- and post-synaptic monoamine receptors. Despite relatively low remission rates and the lag time between treatment initiation and symptom resolution, new drug development has been slow. Much recent research has been devoted to identifying a common mechanism of action of antdepressant drugs that is more closely associated with the temporal sequence of symptom resolution. Moreover, identifying the basic underlying pathophysiology of major depressive disorder (MDD) may elucidate novel targets leading to development of more efficient and effective treatment. &lt;/p&gt; &lt;h4&gt;ABOUT THE AUTHORS&lt;/h4&gt; &lt;p&gt;Elizabeth I. Martin; and Charles B. Nemeroff, MD, PhD, are with the Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.&lt;/p&gt; &lt;p&gt;Address correspondence to: Elizabeth I. Martin, 101 Woodruff Circle, Suite 4000 WMRB, Atlanta, GA 30322; or fax 404-727-3233.&lt;/p&gt; &lt;p&gt;Dr. Martin has disclosed no relevant financial information. Dr. Nemeroff has disclosed the following relevant financial information: American Foundation for Suicide Prevention (AFSP), George West Mental Health Foundation, Mt. Cook Pharma, and Novadel Pharma: Member of Board of Directors; National Institutes of Health (NIH): Research Grant Recipient; AFSP, Astra-Zeneca, Forest Laboratories, Janssen/Ortho-McNeil, Quintiles, NARSAD (National Alliance for Research on Schizophrenia and Depression), and PharmaNeuroboost: Member of Scientific Advisory Board; and CeNeRx, Corcept, Novadel Pharma, PharmaNeuroboost, and Reevax: Equity or Shareholder.&lt;/p&gt; &lt;p&gt;This research was supported by NIH MH-77083, MH-69056, MH-58922, MH-39415, MH-42088, and RR-00039.&lt;/p&gt; &lt;h4&gt;EDUCATIONAL OBJECTIVES&lt;/h4&gt; &lt;ol&gt;&lt;li&gt; Describe how antidepressants, as well as other psychiatric drugs, normalize the disturbances in CRF-containing circuits and HPA axis signaling and that these changes are associated with a favorable treatment response.&lt;/li&gt; &lt;li&gt;Assess how measures of disrupted CRFergic signaling and downstream changes in HPA axis functioning may be used to predict response to antidepressant treatment and risk of relapse. &lt;/li&gt; &lt;li&gt;Determine how individual genetic differences in CRF-related genes may influence predisposition or resiliency to psychiatric disorders as well as likelihood to respond to a given treatment. &lt;/li&gt; &lt;/ol&gt;

(170) Milnacipran is safe and well tolerated in the treatment of fibromyalgia syndrome

Milnacipran is a norepinephrine and serotonin reuptake inhibitor that has been used extensively and safely in >50 countries worldwide. Recently, milnacipran has been shown to significantly improve the pain and other symptoms associated with fibromyalgia syndrome (FMS). This analysis includes safety data collected from 2209 FMS patients enrolled in 3 double-blind, placebo-controlled trials. Patients were randomized to receive placebo (n=652), milnacipran 100 mg/day (n=623), or milnacipran 200 mg/day (n=934), with the length of treatment ranging from 12 to 29 weeks. The safety of milnacipran was evaluated using MedDRA-coded treatment emergent adverse events (TEAEs). The percentages of patients reporting at least 1 TEAE were similar across treatment groups (placebo, 83%; 100 mg/day, 89%; 200 mg/day, 89%).The most frequently reported TEAEs were nausea (placebo, 19.6%; milnacipran 100 mg/day, 34.5%; milnacipran, 200 mg/day, 39.3%) and headache (placebo, 13.7%; milnacipran 100 mg/day, 18.6%; milnacipran 200 mg/day, 17.2%). TEAEs reported in ≥5% of patients and twice the incidence of placebo in either milnacipran group were nausea, constipation, hot flush, hyperhidrosis, palpitations, vomiting, heart rate increased, dry mouth, and hypertension. Discontinuation rates due to TEAEs were 23% and 26% for milnacipran 100 mg/day and 200 mg/day, respectively, and 12% for placebo. In general, there was no evidence for increased frequency of TEAEs with increased dosage. The only severe TEAEs to occur in ≥2% of patients were nausea, headache, and migraine. Similar to other drugs in this class, milnacipran was associated with heart rate and blood pressure increases. The frequency, magnitude, and severity of these adverse events were low and reversible with discontinuation of treatment. Milnacipran is a safe and well-tolerated medication for the treatment of FMS patients. Supported by Forest Laboratories and Cypress Bioscience.

Clinically Relevant Findings from STAR*D

Clinically Relevant Findings from STAR*D

New β-blocker gets FDA approval

A new β-blocker from Mylan and Forest Laboratories was approved in mid-December for marketing in the United States, FDA announced. Nebivolol hydrochloride will be marketed as Bystolic tablets, according to Forest Laboratories, which said it expected to have the product available in U.S. pharmacies