Vol. 7 No. 65
Two Democratic lawmakers are looking into Amgen’s and Johnson & Johnson’s (J&J) advertising and marketing practices for their erythropoiesis-stimulating agents (ESAs).
House Energy and Commerce Committee Chairman John Dingell (D-Mich.) and Subcommittee on Oversight and Investigations Chairman Bart Stupak (D-Mich) say they are concerned that Amgen’s marketing of Aranesp (darbepoetin alfa) in conjunction with Neupogen (filgrastim) and Neulasta (pegfilgrastim) has “helped fuel excessive and dangerous off-label use of Aranesp.” They also say that J&J may have used “misleading” TV and print direct-to-consumer (DTC) ads that include “unsubstantiated” quality-of-life clams to market Procrit (Epoetin alpha).
In letters to the drugmakers, Dingell and Stupak requested copies of ads and other records relating to Aranesp, Neupogen, Neulasta and Procrit. Among the requested documents are copies of Amgen’s contracts with oncologists containing information about discounts on the purchase of Neupogen and Neulasta given to physicians who sell certain amounts of Aranesp and records about future plans for marketing Aranesp. They also ask J&J for records related to print ads featuring former U.S. surgeon general Joycelyn Elders, including the dates the ads were run.
In addition, Dingell and Stupak asked:
This is only the latest negative attention for the products. The Oncologic Drugs Advisory Committee (ODAC) last month recommended substantial labeling changes for ESAs, including Aranesp and Procrit (DID, March 14).
Over the past 12 months, physician labeling for the anti-anemia drugs was updated with boxed warnings instructing physicians not to target patients’ hemoglobin levels greater than 12 g/dL because, under those circumstances, the drugs may shorten overall survival and the time-to-tumor progression in several cancer types (DID, Nov. 9, 2007).
Amgen told DID it would work with the congressmen to provide the requested information and it had already voluntarily suspended DTC advertising of Neulasta. J&J told DID it had stopped advertising Procrit “strictly as a business decision made in 2005” and it had received the request for information and would collaborate with the congressmen. — Yuliya Melnyk
Following reports that Merck and Shering-Plough’s Vytorin is an “expensive placebo,” Sen. Chuck Grassley (R-Iowa) has requested detailed information from the companies.
In a letter to the companies, Grassley writes, “Delaying the release of the results from the [drug’s] ENHANCE trial not only affected medical decisions, but also imposed financial burdens on patients as well as the federal government.” He asks for the names and titles of all key opinion leaders for the trial and a list of all payments made to them during the period of November 2007 to the present, including payment dates, descriptions — whether CME, honorarium, research support, etc. — and amounts.
His request expands an investigation begun last year when House Energy and Commerce Committee Chairman John Dingell (D-Mich.) and Oversight and Investigations Subcommittee Chairman Bart Stupak (D-Mich.) asked the companies to explain their delay in reporting results from the trial, which ended in April 2006 (DID, Dec. 13, 2007). The trial found that Vytorin, which combines Merck’s Zocor (simvastatin) with Merck and Schering-Plough’s Zetia (ezetimibe), was no more effective than Zocor in treating people genetically disposed to having high cholesterol (DID, Jan. 15).
In addition, Grassley wrote to James Dove, president of the American College of Cardiology (ACC) questioning the $5 million the ACC has received from Merck since 2003, more than $1 million from Shering-Plough, and more than $5 million from the joint venture of Merck/Shering-Plough Pharmaceuticals.
Grassley also asks how much was budgeted for marketing and advertising for Vytorin (including direct-to-consumer advertising) since the trial was completed. — Yuliya Melnyk
A new study finds high doses of Celebrex increase the chance of heart attack and stroke and recommends high-risk patients receive low doses of the drug.
Researchers analyzed trial data for three doses of Pfizer’s Celebrex (celecoxib) — a 400- mg once-daily dose, a 200-mg twice-daily dose and a 400-mg twice-daily dose.
They found nearly three times the risk of heart attack, stroke and other adverse cardiovascular events with the twice-daily 400-mg dose compared with placebo and twice the risk with the 200-mg twice-daily dose. Patients on the 400-mg once-daily dose had a 10 percent greater chance of adverse cardiac events.
The results, presented Monday at the American College of Cardiology’s (ACC) annual meeting, showed the risk of celecoxib-related events is linked to patients’ baseline risk of cardiovascular events. This analysis provides “some measure of comfort in prescribing celecoxib in the lowest possible doses to patients at very low risk of cardiovascular events,” lead researcher Scott Solomon said.
Physicians “should be cautious in prescribing celecoxib, especially in higher doses, in patients at high risk for cardiovascular events,” he said, noting that the majority of patients taking Celebrex for arthritis use lower doses than those tested.
The data come from a pooled analysis of six randomized, controlled trials comparing celecoxib with placebo. The primary endpoint was the composite of cardiovascular death, heart attack, stroke, heart failure or thromboembolic event.
After Merck’s Cox-2 inhibitor Vioxx (rofecoxib) was pulled from the market in 2004, researchers were asked to review cardiovascular safety data for other Cox-2 inhibitors, including celecoxib. Long-term use of Vioxx was linked to increased risk for heart attacks and strokes (DID, Oct. 1, 2004).
The analysis provides the most comprehensive assessment to date of celecoxib’s cardiovascular risk, according to the ACC.
Celebrex, a nonsteroidal anti-inflammatory drug, had U.S. sales of $1.7 billion in 2007, according to Pfizer. — April Astor
A federal court Tuesday declared proposed rules on patent claims and continuations to be beyond the authority of the Patent and Trademark Office (PTO), permanently enjoining the rules from going into effect.
The U.S. District Court for the Eastern District of Virginia granted summary judgment to GlaxoSmithKline (GSK), which challenged the legality of the rules last year (DID, Oct. 26). The court had granted GSK’s preliminary injunction motion to stop the rules from going into effect Nov. 1, 2007.
“This is a judgment in support of innovation across all industries,” GSK said of the Tuesday’s ruling.
The PTO issued the rules last August, saying they would speed the patent examination process and improve the quality of patents (DID, Aug. 23, 2007). The rules stipulated that if a patent application contained more than five independent claims or more than 25 total claims, the applicant would have to provide an examination-support document to the PTO.
The rules also modified how many continuing applications parties are allowed to file after submitting an initial application. Any third or subsequent continuation application, as well as any second or subsequent request for continued examination, would have been required to include justification of why the new evidence was not submitted previously.
GSK argued in its complaint that the PTO doesn’t have the authority to promulgate the rules partly because Congress has not yet passed the Patent Reform Act, which would give the PTO rulemaking authority with respect to continuing applications. GSK also asserted that the claims limit is unjust because companies are permitted to file “one or more claims” under law. In addition, the company said the examination-support document and justification requirements are vague and burdensome.
In friend of the court briefs filed earlier this year, PhRMA and the Biotechnology Industry Organization (BIO) said the rules would pose a serious threat to innovative pharmaceutical companies.
BIO President and CEO Jim Greenwood called the ruling “a sound decision” that demonstrates a need to address the workload at the PTO in a way that doesn’t harm innovation. — Breda Lund
Connecticut has sued the FDA in an attempt to force the agency to act on a 4-year-old citizen petition seeking stronger warnings for Purdue Pharma’s OxyContin.
Attorney General Richard Blumenthal filed a citizen petition in January 2004 as a result of an investigation of Purdue during which he found the company had data showing that dosing OxyContin (oxycodone HCl) at intervals of less than 12 hours is hazardous, he said this week.
He also discovered that 20 percent of OxyContin prescriptions were written for dosing intervals of eight hours or less, even though the opioid analgesic is approved only for 12-hour dosing, according to the March 31 lawsuit filed in the U.S. District Court for the District of Connecticut. Many physicians do not understand the drug’s controlled-release delivery system, Blumenthal said.
His petition asked the FDA to strengthen the drug’s warning label with respect to dosing, add information on the dangers of an off-label dosing schedule to the drug’s black box warning and issue a “dear doctor” letter to all prescribers of controlled substances to inform them of the dangers of dosing OxyContin at intervals of less than 12 hours.
The attorney general also requested the FDA disseminate warnings concerning the dosing of OxyContin through a safety alert, public health advisory, talk paper or urgent notice.
Prescribers who don’t understand the dosing regimen for OxyContin are putting patients at risk of addiction or respiratory depression, the attorney general said. Between 1999–2003, there were 49 separate MedWatch reports of deaths among patients taking OxyContin at eight-hour intervals or more frequently, he added.
In the lawsuit, Blumenthal asked the court to declare the FDA’s failure to act on his petition in violation of the Administrative Procedure Act and compel the agency to respond within 30 days of granting declaratory relief.
“The FDA has a legal and moral responsibility to ensure that providers and patients fully understand the potential dangers of improperly prescribing OxyContin,” he said.
The FDA said it does not comment on pending litigation.
Teva Pharmaceuticals plans to appeal a district court ruling this week that it failed to prove that the ’098 patent on Prevacid is invalid or unenforceable.
Takeda Pharmaceutical sued Teva in the U.S. District Court for the District of Delaware after the company filed an ANDA for a generic version of Tap Pharmaceutical’s Prevacid (lansoprazole) delayed-release capsules. Prevacid is a proton-pump inhibitor indicated for treating acid reflux disease. Takeda and Abbott Laboratories recently decided to conclude the Tap joint venture, with Takeda retaining the rights to Prevacid.
At trial last year, Teva argued that Takeda’s ’098 and ’321 patents are invalid due to obviousness and that the ’098 patent is unenforceable due to inequitable conduct, according to the March 31 opinion. Teva conceded that its proposed generic would infringe on the ’098 patent, while Takeda argued that it would also infringe on the ’321 patent.
The ’098 patent covers lansoprazole and expires in May 2009. The ’321 patent, which covers combining lansoprazole with magnesium carbonate to stabilize the compound, will expire this September.
Teva argued that a person of ordinary skill in the art with a goal of making a new proton-pump inhibitor would have arrived at the ’098 patent using knowledge from prior art. But the court found that Teva did not identify motivation within the prior art for making certain modifications to known molecules.
As for the ’321 patent, Teva asserted that Claim 2 is disclosed in prior art, including references to combining benzimidazoles with magnesium salts and stabilizing compounds that degrade in acid. However, the court again found that Teva failed to demonstrate motivation to combine the elements.
The court also disagreed with Teva’s argument that Takeda committed inequitable conduct when applying for the ’098 patent by withholding certain information from patent examiners about the potency of lansoprazole. The court found that Takeda failed to prove that Teva’s generic product would infringe on the ’321 patent. — Breda Lund
A member of the Infectious Diseases Society of American is telling the FDA the current situation with community-acquired pneumonia (CAP) constitutes “a public health emergency” requiring urgent action to remove “uncertainty from the design of clinical trials” for the disease.
David Gilbert, chief of infectious diseases at Providence Portland Medical Center in Oregon, spoke of the urgency to “break the logjam” on CAP trial designs during a presentation Tuesday to the FDA’s Anti-Infective Drugs Advisory Committee.
“Physicians both clinical and academic see an impending disaster and want to get the pipeline moving,” Gilbert said. Although attractive new targets for research exist, drug companies “cannot take financial risk due to unclear regulatory guidance,” he added.
CAP trial designs may demonstrate the superiority of the investigational drug to standard antibiotics or, in case of a noninferiority design, “a substantial treatment effect” that justifies approval of a new drug, Gilbert said. Quantitative endpoints can be used to prove such substantive treatment effects, he added.
However, noninferiority designs “should be avoided if possible because they share many of the inherent dangers of historically controlled trials,” Tom Fleming, professor of biostatistics at the University of Washington, said.
Although valid noninferiority trials of CAP are possible under certain circumstances, Fleming recommended they have all-cause mortality endpoints and recruit from a population with at least 15 percent mortality, and that clinical investigators confirm the presence of pneumococcal pneumonia-like disease through a microbiological examination.
Data from CAP trials “should be reproducible and reliable,” Gilbert said. It is vital that trial designs be feasible in practice, instead of being perfect in theory, he added. Sponsors need to know what trial designs are feasible and ethical.
The FDA and Infectious Diseases Society of America held a workshop on CAP trials in January that concluded placebo-controlled CAP trials are not justified, feasible or ethical because leaving pneumonia patients untreated when effective drugs exist is dangerous (DID, Jan. 22). — Martin Gidron
Data from four-week pooled Phase II trials show that Roche’s investigational cholesteryl ester transfer protein inhibitor R1658 is well tolerated and does not raise blood pressure. The company presented these findings at the 57th Annual Scientific Session of the American College of Cardiology.
Roche is developing R1658 as a treatment for dyslipidemia, a condition that results in abnormal lipid and lipoproteins levels in the bloodstream and an increased risk of cardiovascular disease.
Results showed that after four weeks, R1658 taken alone or in combination with pravastatin, atorvastatin or simvastatin was generally well tolerated and did not cause an increase in cardiovascular adverse events or changes in blood pressure compared with a placebo. Side effects included gastrointestinal disorders, headache and dizziness.
The company presented preclinical data showing that R1658, unlike torcetrapib, had no impact on blood pressure in rats.
Roche said in January that based on results from Phase II studies, it was going to move the drug into Phase III trials.
R1658 was in-licensed by Roche from Japan Tobacco in October 2004 and is being jointly developed by the two companies. Roche has exclusive commercial rights to the drug in all territories except Japan, where Japan Tobacco has retained these rights. — Elizabeth Jones
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