Drug Safety Surfaces Again

Is the FDA adopting a more proactive stance on drug safety issues? Following the withdrawal of Vioxx and the more recent furor over Avandia, the agency has been at the receiving end over drug safety concerns.

Avandia received a black box warning, which still says that the link to cardiovascular risks is not conclusive and advises consulting a doctor regarding continuing treatment with the drug. Sanofi’s Acomplia did not receive FDA approval as it was linked to an increased risk of suicide.

The latest drug to draw attention is the anti-smoking pill Chantix and the FDA is reviewing adverse event reports submitted by the manufacturer Pfizer about the drug. A preliminary assessment found cases where patients experienced "depressed mood, suicidal ideation, and changes in emotion and behavior within days to weeks of initiating treatment".

The agency said the role of Chantix was "not clear" in suicidal cases, because stopping smoking can exacerbate existing psychiatric symptoms, and create nicotine withdrawal symptoms. However, it said doctors should monitor patients taking Chantix for behavior or mood shifts, and patients should contact their doctors if they notice any changes

Chantix is the first drug of its kind to reduce the intensity of nicotine cravings while also making smoking less pleasant. The drug affects dopamine, a chemical in the brain involved in controlling mood and behavior. As dopamine triggers a positive mood response, regulating its levels can remove some of the pleasure derived from smoking.

The FDA is currently analyzing all material submitted by Pfizer and expects to communicate its conclusions and recommendations once its analysis is complete.

James Kelly, analyst at Goldman Sachs, said: "It will be key to watch physician behavior in the wake of this public disclosure, as well as the FDA's future communications, based on additional data and analysis provided by Pfizer."

- D R Sudhakar

Stem Cell Research: Obstacles On The Way

Though many researchers have put their heart and soul to work on stem cell research, they have to face very large obstacles like the ethical and religion issues.

In South Korea, when Hwang Woo Suk, a scientist reported creating human embryonic stem cells through cloning, he did not apologize for offending religious taboos. He justified cloning by citing his Buddhist belief in recycling life through reincarnation.

Cynthia Fox, the author of “Cell of Cells,” a book about the global race among stem-cell researchers said, “Biotechnology has been considered as playing God.”

Cloning human embryos for research has been legally supported in England and several other countries, but it is banned in more than a dozen others, including France and Germany.

Of course, many critics of biotechnology do not explicitly use religious beliefs to justify their opposition. Countries like the United States, are supposed to be guided by secular constitutions, not sectarian creeds. So opponents of genetically modified foods focus on the possible dangers to ecosystems and human health, and committees of scientists try to resolve the debate by conducting risk analyses.

The prospect of cloning children is much more distant, even when researchers are becoming optimistic about obtaining stem cells without using embryos. For now, scientists throughout the world say they do not even want to contemplate reproductive cloning because of the risks to the child. And public-opinion polls do not show much support for it anywhere.

Even if human cloning becomes safe, there may never be much demand for it, because most people will prefer having children the old-fashioned way.

- Roopa S

Anemia Drugs: What Next

It looks like the problems for this group of drugs is unending.

Following FDA scrutiny a revised statement about potential risks of anemia drugs in CKD patients has been approved.

The FDA said the label changes for Aranesp, Epogen and Procrit also include a statement that symptoms of anemia, fatigue and quality of life have not been shown to improve in patients with cancer who take these drugs.

In case of cancer patients, the new boxed warnings stress that ESAs caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer, when they received doses exceeding the prescribed levels.

The FDA also stated that the drugs have been used in patients who apparently had hemoglobin levels of 12 grams per deciliter or higher. However these drugs are to be used to maintain hemoglobin levels of 10 to 12 grams per deciliter for safety reasons.

Smaller doses of the drugs are recommended. There have already been a lot of controversies around the overuse of these drugs.

On another front the anemia drugs face a challenge from Roche’s Mircera that has received FDA approval to treat anemia in kidney failure patients. However, the drug awaits resolution of a patent infringement case before it can be launched.

The launch of Mircera means a significant milestone for Roche while it could turn out to be a nightmare for Amgen, as it threatens to break Amgen’s monopoly.

Roche is considering appealing the decision, while Amgen seeks to obtain an official injunction to stop the sale of Mircera in the U.S. With an injunction in place, Roche probably will not have a chance to sell the product in the U.S. until at least 2012, when the first patents on Amgen's anemia drugs expire. Analysts are certain that Amgen will prevail in the court battle.


- Roopa S

Avandia...? The Uncertainty Continues.

From the very day that Dr. Nissen’s meta-analysis was published on the NEJM associating Avandia to cardiovascular risks, one thing has remained unchanged till date. The issue was uncertain then and even today the uncertainty continues.

While the drug already has a black box warning for heart failure, as does its competitor Actos, and the FDA has asked that a warning about myocardial infarction be added to the existing warning on the label.

This warning however does not say anything categorically and reads thus:

"A meta-analysis of 42 clinical studies (mean duration six months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction," it said. "Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

Janet Woodcock, M.D., FDA's deputy commissioner for scientific and medical programs, chief medical officer, and acting director of the Center for Drug Evaluation and Research, said the FDA is also asking that all oral antidiabetes drugs add this language to the drug labels: "To date, no oral antidiabetes drug has been conclusively shown to reduce cardiovascular risk."

Dr. Nissen, co-author of the meta-analysis that will be inscribed on the rosiglitazone label, said he was satisfied that the FDA added a new black box for ischemic heart disease, but he said the warning was "weakly worded and ambiguous."

There are a lot of questions with no answers and it might be a long time before someone eventually comes up with something conclusive. But till then diabetics around the world and the doctors treating them will remain in the dark.

Dr. Gregory Dehmer, professor of internal medicine at Texas A&M Health Science Center College of Medicine and director of the cardiology division at Scott & White Hospital in Temple summed it up wonderfully, "For the average clinician in the street, there's a substantial amount of uncertainty, and this is magnified for patients."

- D R Sudhakar

Vioxx – The Last Chapter?

The $4.8 billion settlement of Vioxx claims brings what will perhaps be the final steps towards Merck’s putting this issue to rest. This step has been welcomed by the market and plaintiffs’ lawyers and the company is moving cautiously following lessons from the past with a rigorous process for evaluating lawsuits.

Vioxx was pulled from the market in September 2004, after studies linked its long-term use to increased risk for heart attacks. What followed was a flood of lawsuits and it appeared that they would never end.

The risks associated with Vioxx meant that other drugs in the same class – Cox-2 inhibitors - were also subject to intense scrutiny and in April 2005, Bextra was withdrawn because of similar fears. Presently, Celebrex is the only Cox-2 inhibitor to be sold in the United States, and its label carries a black-box warning detailing potential heart risks.

From the time Vioxx was withdrawn from the market, Merck was determined to fight each of the lawsuits. This got the company some key victories which sent a signal to plaintiffs that the odds were against them.

The agreement being worked out by Merck and plaintiffs lawyers aims to resolve the most serious cases, those that resulted in heart attack or ischemic stroke.

However, a lot of questions remain, particularly on how the payments will be shared among the plaintiffs, their lawyers and insurers.

The settlement plan would work thus: Plaintiffs will have to show that Vioxx was taken for at least 30 days. The individual must have suffered a heart attack or ischemic stroke within 14 days of using the drug. The compensation will be lower if the person had cardiovascular risk factors prior to being treated with the drug. Plaintiffs' lawyers can only participate if they recommend the program to all their clients.

Merck will set up two funds, a $4 billion one for heart-attack claims and an $850 million one for stroke claims. The deal will go ahead provided 85% of eligible claims are enrolled.

Merck’s decision has triggered a positive among analysts and Barbara Ryan of Deutsche Bank commented that the company's "aggressive and successful defense strategy has given it a heavy hand in the bargaining process and produced a favorable outcome in the Vioxx settlement, at a cost that is clearly at the low end of general expectations."

Morgan Stanley analysts stated that the deal is "well below initial Street estimates that ranged from $20 billion to $30 billion. We see today's news as a clear positive for Merck as it removes management distraction and ongoing Vioxx-related legal costs."

All this certainly means good going for Merck. Hopefully this should mean that the nightmare that was Vioxx will be a thing of the past and the company can go on into the future without this burden.

- Roopa S.

Beyond Torcetrapib - A Ray of Hope…

The data on torcetrapib presented at the American Heart Association’s (AHA) Annual Scientific Meeting last week at Orlando suggests that while adverse events with all CETP inhibitors cannot be ruled out, other drugs in the same class still warrant further investigation.

Torcetrapib failed a large Phase 3 trial almost a year ago after it was found to actually increase the risk of death. With its leading brand Lipitor already facing competition from generics and its patents due to expire in 2010, torcetrapib was intrinsic to Pfizer’s plans for the cholesterol market and was also expected to provide an extended lease of life to Lipitor.

The aftermath saw billions of dollars being wiped off Pfizer’s value and the industry was left wondering whether the problem was restricted to torcetrapib or it extended across all CETP inhibitors. Merck and Roche halted research on their own CETP inhibitors, till more information was known on why the drug failed.

Data that was eagerly awaited by the medical fraternity and the pharma industry was first discussed at the Annual Session of the American College of Cardiology in March this year.

Commenting on the findings Dr. Steve Nissen said, “Something ‘strange’ is going on with the novel cholesteryl-ester-transfer-protein (CETP) inhibitor. In all three studies, there were dramatic increases in HDL cholesterol and significant reductions in LDL cholesterol, but this improvement in lipid parameters was offset by significant increases in blood pressure.”

He added, "The addition of torcetrapib to statin therapy has no benefit at all on atherosclerosis progression, but it remains to be investigated whether this is a consequence of the molecule torcetrapib or whether the concept of CETP inhibition is a flawed hypothesis. Additional data from the ILLUMINATE study later this year will hopefully shed more light on this issue.”

Merck reiterated that no adverse effect on blood pressure was seen in early studies of its CETP inhibitor, MK-0859 and Roche said it continued to investigate its experimental drug R-1658, and expected to submit it for regulatory approval after 2010.

The Illuminate study findings presented at the AHA meet this month did not show torcetrapib in very good light. While investigators found apparent pointers towards the drug’s impact on blood chemistry, there is still some uncertainty whether the adverse effects were typical of torcetrapib alone or were a class effect.

The initial results from the Illustrate trial showed that although torcetrapib markedly increased good cholesterol levels, it also substantially raised blood pressure and failed to significantly slow the buildup of plaque.

Torcetrapib also produced unexpected "off-target" toxicity on the adrenal gland, which was instrumental in leading to damage of artery walls and increase blood pressure. This off-target effect might hold the answer to why torcetrapib did not work as well as expected and also its toxicity.

This could rejuvenate interest in this class of drugs and comes as a ray of hope to companies like Merck and Roche that had halted development on their own CETP inhibitors till more details were available on the torcetrapib failure.

Presenting data from a new study at the Drugs Affecting Lipid Metabolism Symposium, Merck said its experimental CETP drug anacetrapib (MK-0859) more than doubled levels of HDL cholesterol and did not raise blood pressure or affect the adrenal gland.

Yale Mitchell, director of cardiovascular disease at Merck Research Laboratories said that the company will decide whether to go ahead with their experimental work on receiving and considering the results of further investigations.

Speaking at the Reuters Health Summit in New York, Roche Chief Executive Franz Humer said that they expect to decide in the coming weeks whether to go ahead with a late-stage trial of R1658. He said, "We've looked at the molecule and are very encouraged there is a way forward. We are certainly thinking about an (annual sales) potential of beyond $3 billion to $4 billion" if the drug succeeds in trials and is approved.

Finding compounds that raise HDL cholesterol has been a priority of drug developers as many patients on drugs that lower LDL cholesterol still experience heart attacks, stroke or sudden cardiac death.

Researchers at the AHA meeting said, "Our study neither validates nor invalidates the hypothesis that raising levels of HDL cholesterol by the inhibition of CETP may be cardioprotective. Thus, the possibility that the inhibition of CETP may be beneficial will remain hypothetical until it is put to the test in a trial with a CETP inhibitor that does not share the off-target pharmacologic effects of torcetrapib."

One year from the torcetrapib failure there is still some hope for the CETP inhibitors and they have not been written off altogether.

- D R Sudhakar