Drugs being developed for the treatment of diseases of the central nervous system (CNS take 35% longer to complete clinical trials and receive regulatory approval than other new prescription medicines, according to a new analysis.
Between 1996 and 2010, the mean clinical-plus-approval-phase time for CNS drug treatments approved in the US was 32 months, 35% longer than the mean for non-CNS drugs approved during the same period, according to the analysis, which is published by the Tufts Center for the Study of Drug Development (CSDD .
But despite the longer and more costly development associated with CNS drugs, "the CNS new product pipeline is among the richest in the R&D-based drug industry," comments Joseph DiMasi, who conducted the study and is director of economic analysis at the Tufts Center.
The industry's CNS drug pipeline includes products to treat neurological diseases such as Alzheimer's disease, epilepsy, migraine headaches and stroke, and mental health conditions such as addictions, autism, depression, panic and schizophrenia.
The pipeline has grown by an annual average of 6% over the last decade and currently accounts for 11% of all drug development projects worldwide, the study notes. Nevertheless, development of these treatments poses a challenge for drugmakers, with the clinical approval success rate for "self-originated" CNS drugs entering clinical trials between 1993 and 2004 estimated at about one in 10. That compares to around one in six for all self-originated drugs, according to the study, which goes on to explain that "self-originated" drugs are those developed entirely by one manufacturer, in contrast to compounds which a company may obtain through licensing, purchase or other means.
Also, the "clinical approval success rate" refers to the share of New Chemical Entities (NCEs in clinical development that eventually obtain marketing approval from the US Food and Drug Administration (FDA .
The analysis is reported in the March/April issue of the Tufts CSDD Impact Report. It also reveals that the clinical approval success rate for self-originated CNS drugs varied from a low of 7.1% for products entering clinical testing during the period from 1995 to 2000 to 14.8% - or more than double - for drugs which entered clinical testing during 1998-2003.
It also notes that the mean clinical time for CNS drugs during 1996-2010 was 102.1 months, which is 40% longer than for non-CNS drugs, while the mean approval time for these products was 20.3 months, or 13% longer than for non-CNS treatments.
On February 29, a federal district court judge issued an
Order requiring that Cardinal Health, Inc. comply with an Immediate Suspension Order ("ISO" issued by the Drug Enforcement Administration ("DEA" . The court previously granted a temporary restraining order delaying Cardinal's compliance with the ISO, pending a decision on a preliminary injunction requested by Cardinal. However, the Court denied this preliminary injunction in its Order. Cardinal
appealed this decision on the same day as the court's Order.
Partially at issue in this dispute is the question of who is responsible for stopping diversion, a form of illegal sales of controlled drug substances. Diversion is distributing controlled drug substances to an entity without a valid DEA registration. In this case, diversion of the prescription pain killer oxycodone allegedly took place at pharmacies supplied by Cardinal's Lakeland, Florida distribution facility. Cardinal states that it has a system in place to stop diversion and that it is ready and willing to suspend shipments to any pharmacy that the DEA identifies as likely to be engaged in diversion. The DEA, however, states that the Lakeland facility has a continuing, affirmative obligation to police its retail customers to ensure that the controlled drug substances it provides are not being unlawfully diverted--and the Lakeland facility fell short of its legal and contractual obligations.
According to a
Complaint filed by Cardinal, the ISO requires the Lakeland facility to immediately halt shipments of all controlled drug substances to about 2,700 pharmacies, hospitals, and other customers to prevent alleged imminent danger to the public health or safety. Notably, only Cardinal's Lakeland facility is subject to the ISO. The DEA, however, does not allege that Cardinal itself distributed controlled drug substances to any entity not permitted to purchase them. Instead, the ISO was issued because four pharmacies that were supplied by the Lakeland facility have allegedly distributed oxycodone for illegitimate uses.
On March 2, the United States Court of Appeals for the District of Columbia ordered an administrative
stay on the Immediate Suspension Order ("ISO" issued by the Drug Enforcement Administration ("DEA" against Cardinal Health, Inc.'s ("Cardinal" distribution facility in Lakeland, Florida. This stay postpones the ISO while the court considers Cardinal's emergency injunction
motion, which would halt the ISO pending Cardinal's separate appeal of the ISO. When granting the stay, the court stated that it had not yet considered the injunction motion on its merits. A decision on the merits will likely come soon, however, because the court ordered an
expedited briefing schedule, requiring the DEA's response to the motion by Friday, March 9, followed by Cardinal's reply on Monday, March 12.
The ISO, previously reported
here, suspended Cardinal's registration to distribute controlled substances (such as the pain medication oxycodone from its Lakeland facility to approximately 2,700 customers, including hospitals and pharmacies. Typically, the DEA revokes a registration after providing the registrant notice of the intent to revoke and a hearing. The DEA may issue an ISO without a hearing, however, when there is an "imminent danger to the public health or safety." Here, according to Cardinal, the DEA alleged imminent danger and issued the ISO without notice and a hearing.
Cardinal argues that there was no imminent danger to justify the DEA's action. The ISO did not allege that Cardinal distributed controlled substances to anyone that the DEA had not authorized to receive them. Instead, the ISO alleged that Cardinal sold high aggregate volumes of oxycodone to four pharmacies between 2008 and 2011. But by the time the ISO was issued, Cardinal had already suspended shipments to two of the pharmacies. Cardinal also noted that its shipments to the other two pharmacies had decreased by 80% prior to the ISO, which Cardinal then suspended after receiving the ISO. Consequently, Cardinal argues that its own remedial measures already negated any danger to the public and the ISO is unnecessary pending Cardinal's appeal.
New York Times, Attorney General Lanny A. Breuer said “Taking advantage of his special access as a chemist at the F.D.A., Mr. Liang used sensitive inside information to reap illegal profits in the pharmaceutical securities market. “For years, he exploited his position in the agency to make easy money on the stock market. But today’s sentence shows that easy money has consequences. Investors engage in insider trading at their peril.” According to court documents, Mr. Liang told the judge, "I'm terribly sorry for what I've done.” --- On the Net:
An independent study commissioned by the
Center for Science in the Public Interest (CSPI uncovered 4-methylimidazole, or 4-MI, in Coke, Diet Coke, Pepsi and Diet Pepsi at levels 4.8 times greater than those allowed in beverages in California.
4-MI is a byproduct of the reaction that produces the caramel coloring in brown sodas. The chemical has been found to be carcinogenic in animal studies.
The state of California has banned 4-MI in any amount that could potentially lead to one cancer case in 100,000 people. However the levels found in these 4 leading Cola brands indicated a lifetime risk of 5 cancers out of 100,000, assuming that people drink one soft drink per day. That risk rises to 10 cancers out of 100,000 people who drink only soft drinks containing caramel coloring.
The federal Food and Drug Administration (FDA sets an even more conservative risk limit for contaminant in food additives of 1 cancer in 1,000,000 people. But the study reported rates of 4-MI that are associated with 48 cancers in 1,000,000.
"Coke and Pepsi, with the acquiescence of the FDA, are needlessly exposing millions of Americans to a chemical that causes cancer," said CSPI executive director Michael F. Jacobson. "The coloring is completely cosmetic, adding nothing to the flavor of the product. If companies can make brown food coloring that is carcinogen-free, the industry should use that. And industry seems to be moving in that direction. Otherwise, the FDA needs to protect consumers from this risk by banning the coloring."
In a
letter to FDA Commissioner Margaret Hamburg Monday, CSPI shared the results of its study. The document served as an addition to the group's petition of last year, which called on FDA to ban caramel colorings made with processes that generate 2-MI and 4-MI.
The study also found 4-MI in Dr. Pepper and Diet Dr. Pepper, but at lower levels than the other 4 brands. A sample of Whole Foods' 365 cola had a concentration of 47 micrograms of 4-MI in a can, as opposed to the almost 150 micrograms found in a can of Coca-Cola.
The beverage industry responded to the study by pointing out that the European Food Safety Authority (EFSA , Health Canada and FDA have approved caramel coloring as safe for use in food and drink.
"This is nothing more than CSPI scare tactics, and their claims are outrageous," responded the American Beverage Association. "The science simply does not show that 4-MEI in foods or beverages is a threat to human health. In fact, findings of regulatory agencies worldwide, including the U.S. Food and Drug Administration, European Food Safety Authority and Health Canada, consider caramel coloring safe for use in foods and beverages. CSPI fraudulently claims to be operating in the interest of the public's health when it is clear its only motivation is to scare the American people."
Coca-Cola defended its product.
"Unlike CSPI, The Coca-Cola Company deals in hard facts," said company representative Ben Sheidler in an e-mailed statement to Food Safety News. "Fact: The body of science about 4-MEI in foods or beverages does not support the erroneous allegations that CSPI would like the public to believe. The 4-MEI levels in our products pose no health or safety risks. Outside of California, no regulatory agency concerned with protecting the public's health has stated that 4-MEI is a human carcinogen. The caramel color in all of our ingredients has been, is and always will be safe. That is a fact."
FDA spokesman Doug Karas said the findings of the report were not of concern to consumer health.
"A person would have to drink more than a thousand cans of soda in a day to match the doses administered in studies that showed links to cancer in rodents," he told Bloomberg.
The analysis was limited to 13 samples - 1 of Whole Foods' 365 and 2 of each other brand - all purchased in the Washington, D.C. area.
This article has been updated since its original publication.
"That's not even a quarter of their profits," said Copeland, a law professor at
Pennsylvania State University. "I was up in arms."
Government officials say they are, too, and they've talked about incorporating some of Copeland's ideas.
"That's a question we've been struggling with for the last couple of years," said Gregory Demske, assistant inspector general for legal affairs at Health and Human Services. "We recognize there's a problem."
If a company is excluded from doing business with the government, then medications that only those companies produce will not be available to beneficiaries. But, Copeland said, the fees associated with corporate integrity agreements haven't been enough to keep companies from bilking the government again.
"It's still in the company's interest to promote off-label marketing because they're still going to make more in profits than they lose in fines," she said.
HHS officials are talking with those at the
Justice Department and Food and Drug Administration to fix the problem, Demske said.
Most of the cases come from off-label marketing of prescription medications. For example, Pfizer was accused of marketing Bextra, a painkiller, for uses other than what the
FDA had approved. Such uses constitute fraud because they take government money for purposes the FDA has not approved.
Instead of excluding an entire company from doing business with the government, Copeland said, the drug being marketed off-label could be excluded.
HHS officials considered that, Demske said, but they needed to ensure that beneficiaries could get their medications. The agency is considering taking away a company's patent rights as part of a settlement with the government.
That, he said, would allow other companies to make and sell the drugs to the government. Such a deal could be negotiated with companies as part of a fraud settlement and would not require congressional approval.
"We could require other things if the defendant will agree to it," he said. "If not, there might not be a settlement."
And if there's no settlement, there may be an exclusion.
Copeland suggested requiring companies to conduct clinical trials for the off-label uses they were accused of, requiring that they license a product to other manufacturers and holding high-level individuals criminally liable. Demske said that investigators began going after individuals in companies in 2010 and that they have focused resources on that idea.
Pfizer,
Bristol-Myers Squibb and
Abbott Laboratories did not respond to questions from USA TODAY.
"Imposing such a severe penatly on a person who had no knowledge of the wrongdoing at issue is manifestly unfair and unjust," said
Matthew Bennett, senior vice president of the Pharmaceutical Research and Manufacturers of America.
The Supreme Court ruled in the 1970s that the government may go after officials who should have knowledge that fraudulent behavior is happening under their management. However, the law applies only to individuals holding a position at a company.
"If they leave, we can't reach them," Demske said. "The law is written in present tense."
The government has to send a note notifying the person that it is considering excluding them, which leaves the person plenty of time to leave the company.
"They would be free to work elsewhere," Demske said.
A bill to address the problem passed the House last year but hit the Senate too late in the session to make it to a vote. A new bill, HR 675, has been introduced.
Officials with the Centers for Medicare and Medicaid Services are looking for answers, said Ted Doolittle, deputy director of CMS' Center for Program Integrity. Instead of excluding a company, the CMS can revoke payment, which the government plans to do more aggressively, he said.
Last month, 78 home health care agencies in Texas were suspended in connection with a fraud case, and Doolittle said the CMS will not pay them for services until they are cleared of wrongdoing. First, he said, the CMS had to make sure beneficiaries would be able to get the services they need if those centers were out of business.
Congress members have suggested mandatory exclusions for crimes, but Copeland said the cases often don't reach that point because the parties settle before a proclamation and because the government has to worry about patient access.
If the government targeted individuals more aggressively, that could send a powerful message to drug companies, said Stan Twardy, leader of law firm Day Pitney's health care compliance group.
"Something called a jail is going to send a lot stronger signal than a fine," he said. "The regulations can change, but individuals and companies will take advantage of any loopholes they may find. It's part of that game of maximizing profits."
Under a system of agreements and fines, he said, the corporate culture will remain the same.
Copeland said she doesn't think that's enough.
"If you go after the sales manager because the sales manager could have prevented the fraud, it doesn't change the corporate culture," she said. "The more prescriptions, the more money you make, so the incentive remains."
Patrick Burns, spokesman for the non-profit Taxpayers Against Fraud, said although there may be differences of opinion, there is a greater sense or urgency about fighting the problem.
"We're all thinking the same thing," Burns said of investigators and Congress members. "The good news is they're pushing to actually do it."
According to a study conducted by researchers from New Zealand, a number of
Pradaxa side effects are caused by prescribing errors. On March 1, 2012, a letter was published in the New England Journal of Medicine stating that 25% of the injuries caused by Pradaxa are due to prescribing errors.
Traditional blood thinning medications, such as warfarin, contain a reversing agent. This has led researchers to suggest that the adverse side effects of Pradaxa and other new blood thinners could be reduced if there was a reversing agent present.
The Food and Drug Administration issued a safety announcement in 2011 noting the importance of paying close attention to the proper method for storing Pradaxa and also included prescribing recommendations to healthcare professionals.
Pradaxa (dabigatran is prescribed to treat atrial fibrillation not caused by a heart valve problem and is included in a class of drugs referred to as “direct thrombin inhibitors.” Atrial fibrillation is a condition in which part of the heart does not beat properly. Because of this, blood cells form into clots, and travel throughout the body. A stroke may occur if the blood clots reach the brain and a pulmonary embolism may occur if the blood clots travel to the lungs.
The FDA approved Pradaxa in October of 2010. Shortly after the FDA approved Pradaxa for the treatment of atrial fibrillation a number of adverse side effects were reported. Side effects include internal bleeding, gastrointestinal bleeding, brain hemorrhaging, heart attack, and death.
Though no recall has been issued on Pradaxa, the FDA is currently in the process of investigating internal bleeding claims. So far, more than 500 bleeding cases were reported as a result of Pradaxa use, and only 176 bleeding cases were reported with use of warfarin.
No
Pradaxa lawsuit has been filed, however, attorneys are investigating and reviewing claims brought forth by victims who claim Pradaxa caused them to suffer adverse side effects.
statement. “The coloring is completely cosmetic, adding nothing to the flavor of the product. During the chemical analyses, CSPI collected samples of Coca-Cola, Pepsi-Cola, Diet Coke, Diet Pepsi, Dr Pepper, Diet Dr Pepper, and Whole Foods 365 Cola from Washington D.C.-area stores. The group said Pepsi's products had 145- to 153-micrograms (mcg of 4-MI in two 12-ounce cans, while Coca-Cola had between 142- to 146- mcg per 12 ounces in the samples. The state of California has a 29-microgram limit for 4-MI, and drinks that exceed this number may be required to bear a warning notice. CSPI estimates that Coke and Pepsi products have caused about 15,000 cancers in the U.S. "If companies can make brown food coloring that is carcinogen-free, the industry should use that," Jacobson said. "And industry seems to be moving in that direction. Otherwise, the FDA needs to protect consumers from this risk by banning the coloring.” CSPI said the FDA has an exception for contaminants of food additives if it only causes a risk of one cancer in one million people. However, even Dr. Pepper and Diet Dr. Pepper having low levels of 4-MI, about 10 mcg per 12 ounces, pose a cancer risk of seven in one million. "Colorings made with the ammonia or ammonia-sulfite process contain carcinogens and don’t belong in the food supply," Jacobson said. "In any event, they shouldn’t be obscured by such an innocuous-sounding name as ‘caramel coloring." --- On the Net:
A U.S. unit of
Takeda Pharmaceutical Co. (4502 failed to give accurate reports to regulators about hundreds of congestive heart failure cases associated with its diabetes drug Actos, a whistle-blower claimed in a lawsuit.
The company failed to classify “non-hospitalized or non- fatal” congestive heart failure cases as serious from late 2007 to January 2010, former Takeda medical reviewer Helen Ge said in the complaint in federal court in
Boston. Takeda, like other drugmakers, is required to update the U.S.
Food and Drug Administration’s Adverse Event Reporting System.
“These events were not properly identified or reported in the FDA’s safety database,” Ge claimed in the complaint, filed in June 2010 and recently unsealed. “Takeda’s motivation to fraudulently report and under-report the serious adverse events was driven by an economic desire to falsely enhance Actos’s safety profile and to increase sales.”
The case against Takeda Pharmaceuticals North America Inc., filed by Ge on the government’s behalf, became public after the U.S. Justice Department declined to join it on Feb. 22. Twenty- four U.S. states also declined to join Ge’s complaint, said one of her attorneys, Michael L. Baum.
Generic Copies
Takeda, based in
Osaka,
Japan, said Feb. 1 that annual profit will fall 48 percent to 130 billion yen ($1.6 billion in the year ending March 31. Sales of Actos, which generated 27 percent of revenue last fiscal year, declined 19 percent in the previous nine-month period and will slump more when it faces competition from generic copies in August, Takeda said.
Jocelyn Gerst, a spokeswoman for Takeda, didn’t immediately return a call or e-mail seeking comment on the complaint.
Ge’s complaint claims that on “multiple occasions,” Takeda “improperly instructed” its medical reviewers to “change their professional opinion regarding adverse event classifications and assessments.” When she protested, “her contract was summarily terminated,” according to the complaint.
Takeda wanted to make it appear that Actos was safer than GlaxoSmithKline Plc’s Avandia diabetes drug, according to the complaint.
‘Systematic Fraud’
Ge sued under the federal
False Claims Act and similar state statutes, and seeks to recover damages on behalf of governments. She would be entitled to between 15 and 30 percent of any recovery.
“Takeda’s fraud has caused tens of thousands of false claims to be made on federal and state health care programs,” causing “hundreds of millions of dollars” in damages, according to the complaint.
In 2007, the FDA ordered Takeda and Glaxo to place its strongest warning on the labeling of their drugs about the risk of congestive heart failure, a condition that occurs when the heart doesn’t adequately pump blood.
Ge claimed that Takeda’s culture is “riddled with systematic fraud and deceit,” and that the company downplayed data suggesting a link between Actos and bladder cancer.
Baum, of Baum, Hedlund, Aristei & Goldman, said he is undeterred by the
Justice Department’s decision to not join the lawsuit after investigating. The U.S. declines to join four out of five cases filed under the False Claims Act. Companies settle the vast majority of cases when the U.S. intervenes.
“I believe that the documents we obtain in discovery will induce the government to come back in,” Baum said. “But whether they come back in or not, I believe the documents will show that the company violated the False Claims Act.”
One of Ge’s lawyers is
Michael Sullivan of The Ashcroft Group LLC. He is the former U.S. attorney in Boston.
The case is U.S. ex rel. Helen Ge v. Takeda Pharmaceutical Co., 10-cv-11043, U.S. District Court, District of
Massachusetts(Boston .
To contact the reporter on this story: David Voreacos in Newark at
dvoreacos@bloomberg.net
To contact the editor responsible for this story: Michael Hytha at
mhytha@bloomberg.net.
District Judge Richard Leon found that the attempt by the U.S. Food and Drug Administration (FDA to force cigarette makers to display graphic pictures of blackened lungs, rotten teeth and sickly patients on their products was unconstitutional. Carefully pointing out that the burden of proof lay on the side of the federal regulatory body, Leon stated that: “The government has failed to carry both its burden of demonstrating a compelling interest and its burden of demonstrating that the rule is narrowly tailored to achieve a constitutionally permissible form of compelled commercial speech.” Leon also noted that the proposed warning labels, which aim to deter tobacco use, were exaggeratedly large. He also pointed out that the government already has a variety of more effective and targeted weapons for reducing smoking in its arsenal such as cigarette taxes and labels that contain factual medical information rather than macabre images. The Obama administration announced Monday that it would challenge the court’s decision, filing an appeal Monday with the U.S. Court of Appeals for the District of Columbia Circuit. According to legislation passed in 2009, the FDA is charged with the task of making sure that cigarette packaging is equipped with color warning labels in addition to the well-known written warnings from the Surgeon General. The label must cover 50 percent of both the front and back of the cigarette pack as well as 20 percent of advertisements in magazines. A handful of major tobacco companies challenged the law, which was scheduled to go into effect in September of this year. Tobacco giants R.J. Reynolds, Lorillard Inc., Liggett Group LLC and Commonwealth Brands have alleged that the legislation would essentially force them to advertise against the purchase of their own entirely legal products. --- On the Net:
Pfizer director defends virtual trial after recruitment struggle
By Nick Taylor+
06-Mar-2012
Related topics: Clinical evolution, Clinical Development, Phase III-IV
The head of Pfizer's virtual clinical trial has defended the project after its initial failure to recruit patients raised questions about its viability.
Approval of the trial, which allows patients to take part remotely, was hailed as a big step in the evolution of clinical research. However, since gaining approval the study has met problems.
“It didn't recruit”, Miguel Orri, senior director of clinical sciences at Pfizer, said at Partnerships in Clinical Trials in Orlando, Florida. After working towards approval for two years the setback was dispiriting for the Pfizer team.
Orri said problems stemmed from a failure, possibly caused by the team's regulatory focus, to appreciate what patients need. Aspects of the process were “quite complicated and tedious”, Orri said, and Pfizer has learned that patients are still wary putting lots of their health information online.
In response to these realisations Pfizer has revamped the model. A call centre now helps patients through the initial steps and Pfizer is receiving feedback from participants to help shape its plans for the virtual trial model.
Since making the changes Pfizer has seen an “immense inflow of subjects”, Orri said, but the delay means it is behind on its goal of recruiting 600 patients in the US. Despite the setback Pfizer is implementing plans to expand the trial into Europe.
The European trial, REMOTE 2.0, will learn from the mistakes of the US study. Pfizer wants to contract a recruitment vendor to help patients through the initial setup process to end the obstacles experienced in the US.
In a sign that Pfizer is considering the specific needs of the patient population, all participants in the European trial will receive a communication device. The device is like a simplified iPad and the idea is to help patients, particularly older woman from Southern Europe, who spend little time online.
“I don't think we've failed”
In the two years the Pfizer team spent working towards approval it faced internal skepticism, with Orri often being told the project was unfeasible. The struggle to recruit patients could give credence to these views but Orri was quick to defend the trial.
“I don't think we've failed. We have created a new online informed consent process I think we can use in many studies in the future”, Orri said. By taking a modular approach to the methods and tools used in REMOTE trial Pfizer can add effective virtual elements to its other clinical research projects.
The US Food and Drug Administration (FDA encouraged this approach by telling Pfizer to validate all tools used in the trial, Orri said. After talking about the trial FDA officials told Pfizer to “milk the study”, Orri said, and validate techniques for future use.
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