Monthly Archives: March 2011

To compound or not to compound – the FDA weighs in (sort of)

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compounding_250.jpgKV Pharmaceuticals, the St. Louis-based company behind the preterm labor drug Makena, set off a bit of a scare in February by sending a letter to compound pharmacies saying that these pharmacies should stop producing a cheaper alternative of the drug that lacks formal approval from the US Food and Drug Administration (FDA). But yesterday, the FDA announced that it won’t go after these pharmacies so long as the compounded version remains safe and is of good quality.

“In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action […] unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards,” the FDA said in a statement.

The decision sent patients’ spirits soaring — and KV Pharmaceuticals’ stock downwards. Makena, approved last month, costs $1,500 per dose, whereas the drug made by the compounding pharmacies, costs just $10 to $20 per dose. It’s a story not too dissimilar from that of Lucentis and Avastin.

In response to yesterday’s announcement, KV Pharmaceuticals says that Makena is the safest option for patients. But it looks as though the company is taking notice of the controversy surrounding its drug pricing: “It is our commitment that every woman who is prescribed Makena will have affordable access to this FDA-approved and FDA-monitored therapy.”

Even though patient advocates may rally around the FDA’s announcement, it’s worth noting that KV Pharmaceuticals’ concerns about the compounded formulation of the drug are not unfounded. Compounding – the process by which drugs are mixed up when existing versions of medicines are unavailable or are insufficient – does not come without risks. According to the FDA, between 1990 and 2005, 240 severe illnesses or deaths were linked to improper compounding. And studies indicate that many of the prescriptions filled at compounding pharmacies are of insufficient potency.

The question then becomes whether or not it is worth these risks to avoid the nearly $30,000 price tag per pregnancy. What are your thoughts? Please share them in our comments section below.

Image: FDA

UPDATE: Pharmalot reports that in response to the outcry over Makena’s cost this week, KV Pharmaceuticals has lowered the price of the drug by 55%.

Despite steep sticker price, Medicare plans to pay for Dendreon’s cancer vaccine

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The US Centers for Medicare and Medicaid Services (CMS) announced preliminary plans today to provide full reimbursement for Seattle-based Dendreon Corp.’s expensive prostate cancer vaccine Provenge. In a proposed decision memo, the agency said the $93,000-a-year drug was “reasonable and necessary” for men with advanced, hormone-refractory prostate tumors who have minimal or no symptoms of the disease — the stage of prostate cancer for which the drug was approved last April.

“This is a very important milestone,” says Tom Kirk, President & CEO of Us TOO International Prostate Cancer Education & Support, a non-profit organization based near Chicago. “This is a very exciting and attractive option for many men who have limited options with this disease.”

Sean Tunis, director of the Center for Medical Technology Policy in Baltimore and a former CMS chief medical officer, says the decision comes as no surprise as it effectively mirrors the recommendations of a CMS advisory panel that gave Provenge a favorable vote in November 2010. In fact, Tunis argues, “what’s more interesting is what they didn’t do in this policy.” Namely, the CMS did not call for restrictions on reimbursement for off-label use, which could open the door to men with non-metastatic cancers taking the drug.

The proposal is now subject to a 30-day public comment period, and a final decision will be issued 60 days after that.

Seniors are often unfairly excluded from heart failure trials

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copd_l.jpgThe vast majority of people who suffer from heart problems are over the age of 65. Yet many treatments for heart failure are never actually tested in the elderly and without good reason, according to a study published yesterday in the Archives of Internal Medicine.

In a international meta-analysis of 251 clinical trials investigating drugs, devices, and other treatments for heart failure, a team led by Antonio Cherubini of Italy’s University of Perugia Medical School found that almost half of the trials unfairly left out senior citizens due to an arbitrary upper age limit, physical disability or use of other medications.

“Exclusion of older people in clinical trials is still widespread,” Cherubini told Nature Medicine. “We need to change the regulations. We need to put in some sort of requirement to include older subjects in these studies.”

Cherubini acknowledges that including older participants introduces added complexities and costs, but argues that science must “evolve” to meet the needs and realities of ever-ageing populations across the developed world. According to the US Census Bureau, for example, the number of Americans over 65 is predicted to double by 2030.

The project is part of the ongoing EU-funded PaRticipation of the ElDerly In Clinical Trials (PREDICT) research consortium, which aims to promote the inclusion of elderly people in clinical studies. Looking ahead, the PREDICT team plans to develop new clinical trial protocols that accommodate older patients and at the same time, continue to raise awareness about the underrepresentation of the elderly in clinical trials.

Image: NIH

Newborn screening programs need better consent rules, experts say

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Each year, doctors collect blood from more than 4 million babies in the US as part of the routine genetic screening programs required by all 50 states. To ensure accuracy and reproducibility as well as facilitate the development of new diagnostic tests, state public health laboratories retain residual blood samples for later analysis. But according to a new study out this week, most states do not explicitly require that parents are informed that their children’s blood samples are kept or used for research purposes.

“State departments of health that retain dried blood samples and use them for research without specific authorization may be operating beyond the scope of their legal authority,” Michelle Lewis, a research scholar at Johns Hopkins University’s Berman Institute of Bioethics in Baltimore, and her co-authors write in the journal Pediatrics.

In the last two years, the lack of disclosure has led to outrage among parents. In 2009, for example, parents sued the Texas Department of State Health Services, triggering the court-ordered destruction of more than 5 million blood specimens that had been obtained without parental consent. As we reported last year, this action could derail future investigations of birth defect disorders and the development of detection methods.

Now, in a detailed analysis of the laws on all US state books, Lewis and her colleagues show that Texas is one of just eight states that require parents explicitly sign off on their children’s blood samples being used for research purposes.

Lewis warns that secrecy could lead to more parents refusing to participate in newborn screening, which could lead to the under-diagnosis of treatable genetic conditions and curtail invaluable research. “It is vital that state policies regarding the retention and use of residual samples not undermine the public’s trust in state newborn screening programs so that these programs can continue to protect the health of our nation’s children,” she said in a statement.

A public backlash could also jeopardize the fledgling US Newborn Screening Translational Research Network, which was established in 2008 by the National Institute of Child Health and Human Development and the American College of Medical Genetics to help coordinate state screening and research programs and facilitate the long-term study of poorly understood genetic conditions.

Image: Eric T. Sheler / Wikipedia

Schizophrenia consortium beefs up clinical cohort

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Scolnick_250_crop.jpgThe discovery of the antipsychotic drug chlorpromazine more than 50 years ago radically altered the treatment of schizophrenia by giving people a tool to treat the hallucinations and delusions associated with the mental illness. Yet although there are now a number of these first-generation antipsychotics on the market, the medications have limited abilities to reduce the negative symptoms of disease, such as lack of motivation or emotion. Some newer agents that address some of these problems have since been developed, but these carry their own suite of debilitating side-effects, so patients and doctors alike have desperately sought alternatives. To that end, researchers are ramping up their efforts by leveraging state-of-the art sequencing and stem cell technologies to identify better drugs for schizophrenia.

“In the next five years, we are going to understand this disease,” Edward Scolnick, director of the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts, told Nature Medicine. “Nothing but dollars and time stands in our way.”

At the New York Academy of Sciences’ Advancing Drug Discovery for Schizophrenia meeting earlier this month, Scolnick described the latest efforts of the International Schizophrenia Consortium initiative. Two years ago, the consortium — which includes researchers in the US, UK, Ireland and Sweden — conducted a genome-wide association study, and found thousands of common variants linked to the disease. But that analysis was based on only around 3,300 people with schizophrenia and 3,600 healthy controls. Now the group is scaling up to include an estimated 20,000 schizophrenics and 40,000 healthy people in an effort to identify pathways containing a critical subset of these genes that could be targeted to develop new therapies — a strategy that appears promising for a growing number of complex conditions including schizophrenia. Last week, for instance, a separate international team reported in Nature that a polymorphism in the neuropeptide receptor VIPR2, a potentially druggable target, confers significant risk for schizophrenia. A complementary approach using exosome sequencing is also ongoing.

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FDA okays potential blockbuster melanoma drug

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The first drug to extend overall survival for people with advanced melanoma, the deadliest form of skin cancer, won approval today from the US Food and Drug Administration.

“You’ve got a drug that has now shown it’s a consistent winner,” says Vernon Sondak, a surgical oncologist at the H. Lee Moffitt Cancer Center in Tampa, Florida. “And it’s a winner not just in a small way but in a way that’s important to our patients by prolonging their survival.”

In a pivotal phase 3 trial of 676 patients with metastatic melanoma, the drug — a monoclonal antibody called ipilimumab developed by a New Jersey-based subsidiary of Bristol-Myers Squibb — increased lifespan by nearly four months compared to treatment with an experimental vaccine, researchers reported last year. Earlier this week, the company also announced that a combination of ipilimumab and chemotherapy improved overall survival in people with metastatic melanoma more than standard chemotherapy alone.

“There’s no question that this drug prolongs median survival,” says Mario Sznol, a medical oncologist at the Yale Cancer Center in New Haven, Connecticut where around 100 people have received ipilimumab as part of an ongoing compassionate use trial. According to Sznol, a handful of those patients have even experienced long-lasting, durable remissions. “I suspect a small number of patients are cured of their cancer with this drug,” he says.

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Fingering cell dynamics: Zinc fingers let researchers watch cellular action in real-time

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Scientists typically study cells in real-time by introducing glowing reporter proteins into cultured cells and then watching the action unfold under the microscope. But, these probes, introduced at random throughout the genome and expressed at high levels, can interfere with cellular systems and introduce unwanted toxicity.

Now, using enzymes called zinc finger endonucleases that can be engineered to insert glowing probes at specific points in the genome, researchers can more accurately capture cells in action.

“You want [your probe] to report on a process accurately. You don’t want your probe mucking up the process,” says cell biologist David Drubin of the University of California-Berkeley. “So you have to find the right compromise.”

Previous studies indicated that the absorption of proteins at the cell surface is much slower and less efficient in humans than in simpler systems such as yeast. But last month, using cells engineered with zinc finger enzymes, Drubin’s team demonstrated that this type of absorption is actually rapid and efficient, suggesting that the glowing probes previously used threw a wrench in the works.

In future, scientists anticipate that glowing cells such as these could be used to discover new drugs or to assess drug toxicities.

Here, watch two dividing bone cancer cells expressing a green glowing chromosomal protein.

Video: Courtesy of Sigma Aldrich

Sequencing reveals suite of commensal and pathogenic viruses

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phage.jpgVANCOUVER, CANADA — After coming to realize that symbiotic bacteria play a large part in running our bodies, scientists are slowly beginning to appreciate the importance of our viral communities, too. As researchers discussed here earlier this month at the International Human Microbiome Congress, new sequencing techniques are revealing that these viruses — collectively called the ‘virome’ — often differ significantly between healthy and diseased individuals.

“There’s no question that these viral populations are affecting human health,” says Frederic Bushman, a molecular virologist at the University of Pennsylvania School of Medicine in Philadelphia. “But we’re just at an early stage in figuring out who’s there and what they’re doing. Well down the road we’ll be asking how to engineer [the virome] to affect health outcomes.”

Metagenomic studies of viral communities trace their roots back to 2003 when Forest Rohwer and his colleagues at San Diego State University first sequenced the bacteriophage viruses living in a single human fecal sample (J. Bacteriol. 185, 6220–6223, 2003). Since then, newer high-throughput sequencing methods have started to produce vastly more data on many more samples, yet the applications of virome studies to disease are only just starting to be worked out.

To better understand the links between viruses and diet, for example, Bushman and his colleagues placed five people on either a high-fat or a low-fat diet and then sequenced their stool samples over a ten-day period. Reporting at the March meeting, Bushman showed that the bacteriophage populations of people on the same diets grew more similar as the experiment proceeded, raising the possibility that viral communities could be engineered to combat obesity.

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Independent review needed to clarify clinical practice guidelines confusion, experts say

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clintrial2-CROP.jpgClinical practice guidelines are meant to help health care providers weigh the pros and cons of the myriad medical options available. But with more than 2,300 recommendations issued by nearly 300 professional organizations and societies, physicians often don’t know which advice to follow. That’s why the US Institute of Medicine (IOM) is calling for a new approach to developing medical guidances.

In two reports published yesterday, the IOM’s Committee on Standards for Developing Trustworthy Clinical Practice Guidelines and the Committee on Standards for Systematic Review of Comparative Effectiveness Research set out nearly 30 recommendations to steer the guideline-making process. “These standards are necessary given that there is little documentation to the judge the quality and reliability of many of the existing clinical practice guidelines,” Sheldon Greenfield, a health policy researcher at the University of California–Irvine who chaired one of the committees, said in a statement.

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Liz Taylor: activist, actress and clinical trial subject

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Elizabeth Taylor was many things to many people: a screen legend, a social activist, a fashion icon and so much more. But to Abbott Laboratories, the Chicago-based pharmaceutical company, Taylor was also one of nearly 300 study subjects enrolled in the Endovascular Valve Edge-to-Edge REpair Study (EVEREST II), a clinical trial testing an experimental medical device called MitraClip.

In 2009, Taylor, who died yesterday from congestive heart failure at the age of 79, divulged via Twitter that she had received MitraClip, a repair system for treating leaky heart valves. Ted Feldman, a cardiologist at Northshore University HealthSystem in Evanston, Illinois who is leading the EVEREST II trial, told heartwire that he had not been involved in Taylor’s care and didn’t know the details of her treatment. But, he wrote in an email, “our high-risk registry did show decreased rehospitalizations and improved survival for the year after treatment, which may be the case for her.”

Earlier this week, Feldman and his colleagues reported on the healing response of 67 people who received the MitraClip. They found that tissue bridging between the device arms added structural stability to the valve and that the device maintained its mechanical integrity for up five years after implantation. Feldman is slated to announce two-year results from the EVEREST II trial next month at the American College of Cardiology’s annual Scientific Sessions/i2 Summit.

Below you can watch a video in which Feldman describes the experimental technology: