Booster Shots

Oddities, musings and news from the health world

Category: clinical trials

Unpublished FDA study says diabetes drug Avandia should be withdrawn

June 11, 2010 |  2:02 pm

An unpublished study by a Food and Drug Administration researcher and colleagues at Medicare indicates that as many as 48,000 heart attacks, strokes and other cardiovascular problems in the elderly between 1999 and 2009 could have been averted if the patients had taken other medications instead of the controversial diabetes drug Avandia, the Wall Street Journal reported Friday.

The paper by Avandia critic Dr. David Graham has been submitted to the Journal of the American Medical Assn., but the journal has not acknowledged whether it is considering publication.

The Graham study, which reviewed Medicare records, was reported by the respected pharmaceutical industry blog Pharmalot, which also published an e-mail from Graham to his superiors arguing that senior FDA officials were trying to suppress the work.

The FDA is scheduled to conduct a review of Avandia's safety next month.

Previous criticisms of the drug can be found here and here. The group Public Citizen has argued that ongoing clinical trials of Avandia should be halted immediately because of the risks of the drug, as has biomedical ethicist Ruth Macklin.

Stay tuned. The argument is sure to get hotter next month.

-- Thomas H. Maugh II

The FDA approves new drug for Pompe disease

May 25, 2010 | 11:40 am

The Food and Drug Administration on Tuesday approved a new drug called Lumizyme for the treatment of Pompe disease, a disabling genetic disorder that is often fatal. A drug called Myozyme is available to treat the disease, but supplies have been severely restricted and it is reserved for use in children and infants with the most severe form of the disorder. Approval of Lumizyme, which is closely related to Myozyme, will make treatment available to much larger numbers of people.

Pompe disease, which affects about one in 40,000 Americans, is caused by mutations in the gene that is the blueprint for an enzyme called acid alpha-glucosidase, which is used by tissues to convert a form of sugar called glycogen into energy. If the enzyme is not working properly, glycogen builds up in tissues, especially in the heart and muscles, weakening them severely. Many different mutations have been discovered, and they vary in severity. Some mutations produce only a partial impairment in activity and the disease does not become a problem until adolescence or adulthood. In other cases, however, the enzyme does not work at all, and the disorder can be fatal at a very young age unless treated. In infants, symptoms include respiratory problems that often lead to infections, feeding problems, poor weight gain, muscle weakness, floppiness, head lag and an enlarged heart. More than half of victims also suffer enlarged tongues. In the late onset form, the primary symptom is muscle weakness leading to respiratory problems that can be fatal. The heart is usually involved, but it does not become grossly enlarged.

Myozyme, produced by Genzyme Corp. of Cambridge, Mass., is a synthetic form of alfa-glucosidase that breaks down the glycogen, easing Pompe symptoms. The company originally produced the drug in 160-liter batches, which limited the available supply so that its use had to be restricted to infants and children who were most severely affected. The company applied to the FDA to manufacture the drug in 2,000-liter batches, but the agency determined that the synthetic enzyme produced in the larger batches was slightly different from the original product. Apparently, more sugar molecules are attached to its surface. The company was thus forced to conduct clinical trials of the new form, which it chose to call Lumizyme. The safety and efficacy of the drug was demonstrated in a trial on 90 late-onset patients ages 10 to 70, and the FDA granted approval. An estimated 200 adult patients in this country are already receiving the drug on a compassionate basis, and it has already been approved in several other countries.

Because it is a protein, the drug has to be administered by infusion. The primary side effects are allergic reactions to the drug, which include hives, diarrhea, vomiting, itchy skin, skin rash and chest discomfort. The drug will carry a so-called black box warning cautioning about the possibility of severe allergic reactions. The company will undertake a post-marketing surveillance program to monitor for side effects, and the drug will be available only through a restricted distribution system to ensure that it reaches the proper patients, the FDA said.

-- Thomas H. Maugh II

A kinder, gentler colonoscopy

May 2, 2010 |  5:00 am

Preparation for a colonoscopy could soon be substantially easier if research by a Detroit gastroenterologist is confirmed.  Dr. Chetan Pai of the Henry Ford Hospital reported Sunday at the Digestive Diseases Week meeting in New Orleans that it may not be necessary to consume the large amounts of unpleasant liquids now required to prepare for the procedure, which will be a major relief to anyone contemplating it.

Colonoscopies are a highly effective method of both detecting and preventing colorectal cancer. A flexible tube is inserted through the rectum and a miniature television camera is used to view the entire inside of the colon. Polyps, precursors of tumors, can be snipped out when they are found. This procedure is relatively painless because it is typically done under sedation and the patient doesn't feel a thing. An estimated 146,000 cases of colorectal cancer are diagnosed each year in the United States and nearly 50,000 die from it. But early detection can sharply reduce the mortality.

Ah, but getting ready for it is another story. For the procedure to be effective, it is important to clear out all the fecal matter from the intestines. That is done by inducing diarrhea. In the past, that was done with phosphosoda, which was unpleasant to drink, but didn't require more than a couple glassfuls. But doctors found out that phosphosoda was dangerous, so now the laxative of choice is Go Lightly, a solution of polyethylene glycol. Generally, physicians recommend at least a gallon of the solution. But the solution is hard to swallow in adequate quantities, especially for older people. "Even my own family don't want to get colonoscopies" because the preparation is so unpleasant, Pai said.

Anecdotal evidence suggests that the problem can be avoided in part by using lubiprostone, a pill that is normally used to overcome constipation. Pai decided to conduct a clinical trial to see if it worked.

He enrolled 102 patients with an average age of 57 who were scheduled to have a colonoscopy. Half were given lubiprostone--one tablet two days before the procedure and one tablet with each meal the day before the procedure--and half a placebo. All were also given Go Lightly and told to continue drinking it until they achieved a clear bowel movement.

Those who took the lubripristone, sold under the brand name Amitiza, drank significantly less Go Lightly, Pai said. Some were able to consume as little as one 8-ounce cup. Physicians who didn't know which regimen the patients received found that the preparation quality was virtually identical for the two groups and that there was not any difference in the detection of polyps.

The study was funded by Sucampo Pharmaceuticals Inc., which manufactures Amitiza.

-- Thomas H. Maugh II

New treatment kills head lice ... and keeps them dead

February 26, 2010 |  2:15 pm

Mayonnaise, olive oil and petroleum jelly are popular home remedies for suffocating head lice and, at first blush, they appear to work. Unfortunately, lice have external structures called spiracles that protect the entry points to their breathing apparatus. Closing the spiracles protects the lice from the suffocating effects of the home remedies and, when the agent is removed, the lice often appear to have a miraculous resurrection.  A newly approved over-the-counter drug called Ulesfia seems to get around this problem by shocking the spiracles open, according to a report in the journal Pediatric Dermatology.

Of course, over-the-counter products containing the neurotoxin permethrin and prescription drugs containing malathion and lindane are also available. Because these contain neurotoxins, however, they can be used only every 10 days or so and are not appropriate for very young children. Reinfestation often occurs much quicker and the lice, furthermore, appear to be developing resistance to the pesticides.

Ulesfia, manufactured by Shionogi Pharma Inc. of Atlanta, is based on a lotion that suffocates the lice, but it also contains a 5% concentration of benzyl alcohol that shocks the spiracles open. Phase 2 and phase 3 clinical trials conducted for Shionogi by  the drug-testing company Global Health Associates of Miami compared use of Ulesfia to use of the lotion only in 250 children with head lice. A caregiver applied the lotions to the hair for 10 minutes at the beginning of the study and a week later. Company president Terri L. Meinking and her associates reported in Pediatric Dermatology that 91.2% of those using Ulesfia had no lice on Day 8 and 75.6% had none on Day 14. Among those using only the lotion, 27.9% had no lice at Day 8 and 15.5% had none on Day 14.  Irritation of the application site was the most commonly reported side effect, affecting 2.3% of users. 

"Because benzyl alcohol lotion kills by suffocation, resistance should not be an issue," Meinking said in a statement.

-- Thomas H. Maugh II

What, exactly, is Actovegin?

December 15, 2009 |  5:20 pm

The drug made a media debut today when it was reported that Canadian physician Anthony Galea, who has previously treated Tiger Woods, is under investigation by the FBI for giving athletes performance-enhancing drugs.

According to news reports, Galea was arrested Oct. 15 by Canadian authorities – officials said they had earlier found human growth hormone, Actovegin and two other drugs in a medical bag in his assistant’s car. Actovegin, which is essentially calf’s blood extract, has been used in the treatment of circulatory disorders but has not been approved for sale in the U.S. by the Food and Drug Administration.

Actovegin isn’t really one of your known quantities – there’s no mention of it at the FDA website. By contrast, “human growth hormone” turns up more than 2,000 hits. It’s sold by Nycomed, a Swiss-based company. From the product description:
Actovegin® produces an organ-unrelated increase of the cellular energy metabolism. The activity is confirmed by measurement of the increased uptake and of the elevated utilization of glucose and oxygen. These two effects are coupled and they result in a rise of the ATP-turnover and thus in a greater provision of energy in the cell.

“We don’t have it on our books,” said Karen Riley, a media officer with the FDA. “It would have to go through an FDA approval process, and I don’t have any record of that product.”

One might begin to suspect that calf blood extract is another way of saying "snake oil," but wait turns up one hit – a recent trial related to polyneuropathy, or nerve malfunctions in the extremities. It was performed under Russian authority, in Kazakhstan.

Why is it on a U.S. site devoted to clinical trials? “I don't know, I was surprised to see it,” Riley said.

Want to find out if all your prescriptions pass muster? The FDA provides some guidelines here.

-- Amina Khan

Cancer deaths down, but statistics are sticky

December 8, 2009 |  4:06 pm

Our hard work to live more healthfully seems to have paid off, with a new annual report showing that cancer death rates have been dropping since the 1990s. The risks are still higher for men than for women, but men showed the greater drop in deaths, falling 10% from 2002 to 2006 as opposed to 7.5% for women.

Consider also that in 2009, more than 713,000 women and 766,000 men are projected to be diagnosed with cancer, lead author Brenda K. Edwards of the National Cancer Institute said in an interview.

Each year, the report takes an in-depth look at one particular type of cancer to draw conclusions about the why, not just the how much, of cancer death rates. This year, the team looked at colorectal cancer. Aside from being the second most deadly cancer threat, it serves as a good model for studying the declining cancer rate.

Researchers found about half of the decline was due to better screening, Edwards said. (Last year, the report singled out the No. 1 killer, lung cancer, and the team was able to point to smoking controls in California for its comparatively better lung cancer rates.) 

Edwards also raised some concerns that overall numbers would mask certain issues – for example, that lung cancer for women is still on the rise, though it’s going up more slowly than before.

The report, published online in Cancer, is a joint effort of the institute, the American Cancer Society, the Centers for Disease Control and Prevention and the North American Assn. of Central Cancer Registries.

David Agus, director of the USC Center for Applied Molecular Medicine, said in an interview that better screening practices, technologies and healthier lifestyles have contributed to the decline, but he also delivered a reality check on the data.

“This is not acceptable. We need to be down like heart disease, stroke, infectious disease, where the rates are down 50%,” Agus noted. “In the cancer world we’re not much better at doing things than we were five decades ago.”

-- Amina Khan

Company seeks FDA permission to conduct clinical trial using human embryonic stem cells

November 19, 2009 | 10:00 am

Patients with a rare eye disease could be the first to be treated with human embryonic stem cells.

Advanced Cell Technology Inc., a Santa Monica-based biotech company with labs in Massachusetts, announced today that it has asked the U.S. Food and Drug Administration for approval to test retinal cells grown from stem cells in 12 people with Stargardt’s macular dystrophy.

Act The disease is a childhood version of macular degeneration and affects about one in 10,000 kids. Patients typically begin to lose their central vision between the ages of 6 and 20. As SMD progresses, things may look blurry and distorted, and patients may have trouble adjusting to low light. About half of victims are legally blind by age 50. There is no cure.

Most cases occur when children inherent a faulty version of the ABCA4 gene or the CNGB3 gene from both parents.  As a result, the photoreceptor cells in the retina don’t get enough fuel, and they atrophy.

ACT hopes to reverse this by supplying patients with new retinal pigment epithelium cells derived from human embryonic stem cells. The RPE cells have been shown to improve vision in animals, with one study restoring eye function in sick rats and mice to “near-normal” levels. Another study boosted rats’ vision to 70% that of healthy animals. No adverse side effects were found in any of the company’s pre-clinical studies, Dr. Robert Lanza, ACT’s chief scientific officer, said in an interview.

ACT proposes a Phase I/II trial designed to assess the safety and tolerability of its RPE cells. The company and its collaborators would like to recruit a dozen patients with advanced SMD at three sites: the Casey Eye Institute in Portland, Ore.; the University of Massachusetts Memorial Medical Center in Worcester; and the UMDNJ – New Jersey Medical School in Newark.

Amid much fanfare, Geron Corp. received FDA approval in January to use specialized nerve cells made out of human embryonic stem cells to treat a handful of patients paralyzed by spinal cord injuries. Those plans are on hold while the company conducts pre-clinical studies to address some safety concerns about its cells, known as GRNOPC1. Last month, Geron said it expected to initiate its clinical trial in the third quarter of 2010.

Since their creation in 1998, human embryonic stem cells have been a highly controversial area of medical research. The cells are derived from days-old human embryos, which gives them the ability to grow into any type of cell in the body. Some scientists – like those at ACT and Geron – envision using them to grow replacement tissues to treat sick patients. But many people are troubled by the fact that the stem cells are typically made by dismantling and destroying human embryos.

ACT has tried to sidestep the ethical debate by using a different method to create its stem cell lines. Instead of using an entire embryo, the company figured out a way to remove only a single blastomere cell from a three-day-old embryo and turn it into a cell line. Such single-cell biopsies are routinely performed in fertility clinics to screen embryos for devastating genetic diseases, and the procedure leaves the embryo intact. The RPE cells that would be used in the clinical trial were grown from one of the company’s single-blastomere cell lines, Lanza said.

The company is also making and testing RPE cells derived from induced pluripotent stem cells. So-called iPS cells behave like embryonic stem cells but are made by reprogramming mature cells taken from children or adults, not from embryos. However, the reprogramming process currently involves viruses and genetic manipulation techniques that make the cells unsuitable for human therapies.

Lanza said ACT decided to target Stargardt’s macular dystrophy first because it has been designated an “orphan disease” and could benefit from a faster regulatory review. The FDA has 30 days to respond to the company’s filing, made Wednesday, and the clinical trial could begin early next year.

If all goes well, the company plans to seek permission to use its RPE cells to treat age-related macular degeneration, Lanza said. That disorder is much more common, and it destroys the central vision of an estimated 1.75 million Americans.

-- Karen Kaplan

Photo: Scientists from Advanced Cell Technology remove a single cell from a days-old embryo, which was used to create a line of human embryonic stem cells. Stem cells made this way were grown into eye cells that the company hopes will treat patients with Stargardt's macular dystrophy. Credit: Associated Press photo/Advanced Cell Technology

What researchers don't want you to know about their clinical trials

October 26, 2009 |  1:01 pm

Clinical trials can tell us whether new drugs or medical procedures work better for patients than the old ways of doing things. They can also tell us whether a new treatment is dangerous. But medical researchers routinely emphasize the upside of the intervention they studied while glossing over its risks for patients, according to a new report.

Vioxx “The reporting of harm is as important as the reporting of efficacy in publications of clinical trials,” a group of French researchers wrote in a study being published in Tuesday’s edition of Archives of Internal Medicine. “However, harm is frequently insufficiently reported.”

How insufficiently?

The researchers examined 133 studies published throughout 2006 in five of the most influential medical journals – New England Journal of Medicine, Lancet, Journal of the American Medical Assn., British Medical Journal and Annals of Internal Medicine. Of those studies, 83% assessed new drugs, and 55% were funded in whole or in part by for-profit companies.

A total of 15 studies, or 11%, made no mention of any adverse events whatsoever, the researchers found. An additional six studies mentioned adverse events but didn’t provide any numerical data about them.

Even when articles did include hard numbers, they were often presented in a distorted way. For instance, 36 studies didn’t distinguish between minor and severe side effects. Seventeen studies reported only the most common side effects, and an additional 16 included only the most severe. Five of the studies restricted themselves to the side effects that were linked to the drug or treatment being studied in a statistically significant way. (Such side effects are rare, since clinical trials aren't designed to detect them.)

The numbers can also be distorted by focusing on the number of study participants who had an adverse reaction instead of giving the total number of adverse reactions. Of the 90 studies that included numerical data on side effects, 31 did this, according to the French researchers.

Only 17 articles described adverse events that prompted volunteers to withdraw from studies; 63 gave no data on such withdrawals, the researchers found.

The Consolidated Standards of Reporting Trials (a.k.a. “CONSORT”) was amended in 2001 to emphasize the necessity of reporting “all important adverse events or side effects.” But clearly, the French team concluded, “the reporting of harm remains inadequate.”

Dr. John Ioannidis of the University of Ioannina School of Medicine in Greece, was one of the first researchers to study the way safety data are conveyed in medical journals. In an editorial accompanying the French study, he attributed some of the under-reporting to companies intent on “silencing the evidence” that their products could be harmful to patients.

Ioannidis singled out the cases of Vioxx, a painkiller that was withdrawn from the market because it doubled the risk of heart attack and stroke, and Neurontin, an epilepsy drug that the Food and Drug Administration linked to an 80% increase in suicidal thoughts and behavior.

“In these cases,” he wrote, “marketing needs prevail over scientific accuracy and clinical prudence.”

-- Karen Kaplan

Photo: If the side effects of Vioxx were more accurately reported during clinical trials, some deaths may have been averted. Credit: Daniel Hulshizer/Associated Press


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