Assessing the Long-Term Risks of Drugs

Here’s a dilemma for you; drugs that prevent or treat chronic diseases and that therefore will probably be taken for the rest of the patient’s life are generally only tested for a only a couple of years (for safety and efficacy) before they are approved. What if the drugs have adverse effects that only become apparent when they have been taken for many years?

This concern has been raised recently by the discovery that two blockbuster drugs do in fact have long-term negative effects not seen in their initial safety studies. The class of drugs known as bisphosphonates (Fosamax, Actonel, and Boniva) widely used to prevent osteoporosis can, on rare occasion, lead to degeneration of the jawbone or to thigh fractures. And a drug called Avandia, often prescribed for diabetics to prevent heart disease, has been shown to increase the risk of heart disease in certain cases.

I'm not saying that FDA approval of these drugs in the first place was a mistake, because in some cases the benefits may still outweigh the risks. Still, it would be nice to know the long-term risks as soon as possible so that patient treatment decisions can be made with full information. The question becomes, then, how to reduce the potential long-term risk without making the drug approval process even longer than it already is. Requiring 30 years of clinical trials before a drug can be approved is clearly impractical.

Once a drug is approved, currently there is no method for effectively tracking the incidence of adverse side effects over time. Some health officials are suggesting that we develop a national drug-use database and require physicians to report all adverse effects, so that long-term effects can be determined as soon as possible. But that raises concerns over confidentiality of patient information.

What do you think?

Drug Safety in the Workplace

Should a company be permitted to fire a worker for taking a drug that is legally prescribed by a physician to treat a medical condition? That’s what happened to a worker on an auto-parts assembly line who was taking hydrocodone for back pain, according to an article in The New York Times.

You might say, “That’s not fair!”, but it’s not that simple. After all, companies have a responsibility to maintain a safe work environment. Companies can be held responsible for accidents on the job and for product defects caused by impaired workers. And in “safety-sensitive” jobs, such as airline pilot, the public has a right to expect that the employee is not impaired.

The question becomes, then, how does society achieve the right balance between the rights of workers and the responsibilities of employers? At present we know very little about just how safe various prescription drugs are in the workplace, because testing for workplace safety is not part of the normal approval process for pharmaceutical drugs.

More and more companies are requiring drug tests of their employees. Employees who test positive are sometimes fired, in part because companies aren’t sure whether or not the drug creates a safety issue and just aren’t willing to take the risk. It’s a societal problem that needs to be addressed by valid scientific research into drug safety in the workplace.

Potential Alzheimer's Drug Flames Out

A closely-watched drug that was supposed to offer hope to Alzheimer’s sufferers failed miserably in Phase III trials this month, according to a press release from Pfizer, one of the pharmaceutical companies involved in its development. In all likelihood all further research on the drug will stop.

It wasn’t supposed to end like this, although looking back it may not be as surprising as it sounds. The drug, called Dimebon, was actually an antihistamine previously sold only in Russia. The Phase I and Phase II trials (efficacy in animals and limited safety tests in humans) were performed in Russia, and then the drug was patented and brought to the United States for Phase III trials and future marketing as an Alzheimer’s treatment. Apparently it doesn’t work.

Although people sometimes complain (rightly) that the drug approval process in the United States is expensive and time-consuming, there’s a good reason for the process. It protects us all.

Percocet, Vicodin May be Banned

A federal panel of experts advised the Food and Drug Administration (FDA) this month to ban two popular prescription painkillers, Percocet and Vicodin, from the market. The panel also recommended that the maximum allowable dose of acetaminophen in over-the-counter pills such as Tylenol be reduced from 500 mg to 325 mg. The FDA is expected to accept the panel’s recommendations.

Percocet and Vicodin are comprised acetaminophen plus a narcotic. According to the panel of experts, there is now sufficient evidence to conclude that high doses of acetaminophen over prolonged periods of time can cause liver damage.

It's worth noting that nearly all drugs, even some very good ones, can have unwanted side effects if they are abused.

You can read or see the news reports on the panel’s findings by Googling “FDA”, “Percocet”, and “acetaminophen”.

Young Adults Turn to Sleeping Pills

Prescriptions for sleep medications increased nearly 50% in adults under the age of 45 between 1998 and 2006, according to a report in The New York Times. Among young adults aged 18-24, the use of heavily-advertised prescription sleep medications such as Ambien CR and Lunesta nearly tripled. These drugs truly are safer than older, benzodiazepine-based products, so there would seem to be little reason not to use them to get a good night's sleep.

However, in some cases these drugs may be prescribed too readily. Many of these prescriptions are written when the patient is being seen for something other than a sleep disorder, such as a general medical examination or a menstrual disorder. The worry is not the safety of the drugs per se, but that patients may not be receiving much-needed medical workups to eliminate potential underlying psychiatric disorders before prescriptions are written.

If all you want is a good night's sleep, what about adjusting your behavior or environment a little? You might just get a good night's rest if you were to move out of that noisy dorm and stop drinking 6 cups of coffee a day! Just a thought.

Losing the Battle Against Bacteria

Bacterial resistance to antibiotics is increasing and there are too few new antibiotics in the drug discovery pipeline. Nevertheless, more than half of the major pharmaceutical companies have shut down their antibiotics R&D divisions entirely within the last 20 years. Read about it in the current issue of Science (“The Bacteria Fight Back”, Science 321:356-361, July 18, 2008). The article documents the history and the biology of bacterial resistance to antibiotics. It also and suggests some reasons why pharmaceutical companies seem disinterested in developing new antibiotics, even as the human death toll rises.

This would be a good article to share with your students in support of the Health Watch box on page 18 of Human Biology, 5th ed. The article could also be used to kick off a class discussion of the economics of developing and selling pharmaceutical drugs.

Human Drugs From Plants

Remember Cerezyme, that very expensive drug that can cost patients up to $300,000 per year? (See this blog, March 17, 2008.) Cerezyme is a human enzyme called glucocerebrosidase. It is missing in patients with a rare genetic disorder called Gaucher’s disease, found mainly in persons of Ashkenazi Jewish descent.

There may be good news for Gaucher’s disease sufferers soon. An Israeli company named Protalix Biotherapeutics has developed a protocol for producing recombinant glucocerebrosidase cheaply in large amounts. But they’re not using animals – they’re using genetically engineered carrot cells grown in cell culture in big plastic bags. The enzyme is already in Phase III clinical trials, meaning that it is being tested in human patients. If approved by the FDA it will be the first plant-made recombinant drug ever approved for use in human patients. This could be a breakthrough that leads to a whole new field in drug development – making drugs by inserting human genes into plant cells.

To read more about it and see a photo of the carrot cells in culture, go to Protalix’s website at www.protalix.com.

How Do RNA Interference Drugs Work?

A new drug discovery field called RNA interference is hot, hot, hot these days. According to current theory, small snippets of RNA with just the right sequence should be able to interfere with the expression (translation) of genes with the corresponding complementary nucleotide sequence. Drug companies are racing to find the RNA sequences that would inactivate specific disease-causing genes. Presumably the therapeutic effect would be highly specific, since only certain genes would be inactivated.

But is that how the RNA interference drugs currently under development actually work? New evidence just published online in Nature on March 26 (doi:10.1038/nature06783) suggests that the drugs may be working by a much more general mechanism – activation of the immune system. If so, the drugs may have side effects that have not yet been considered. The findings were such a surprise that the stock prices of small companies working on RNA interference drugs went down briefly.

The Nature article is for experts only. For students, I suggest the more general New York Times article published online on Apr. 2 (“Study is Setback for Some RNA-Based Drugs”, http://nytimes.com/2008/04/02/business/02place.html).

A REALLY Costly Drug

A drug called Cerezyme has become a topic of debate among health care professionals, insurance companies, and patients. That’s because at the recommended dosage, the drug costs up to $300,000 per year.

Cerezyme is used to treat a rare inherited disorder called Gaucher disease, characterized by severe deterioration of bones and joints. The recommended dosage was determined on the basis of a clinical trial in only twelve patients more than 15 years ago. At the recommended dosage the drug has proven to be quite effective. But would a lower dose work just as well? Many doctors and insurance companies think so, but the manufacturer (Genzyme) has no interest in finding out. And why would they, when the drug has annual sales of over a billion dollars? Genzyme says it’s not their issue; they’d leave it up to doctors to determine whether a lesser dose would work just as well in their patients.

If the drug were cheap, dosage wouldn’t be an issue. But insurance companies are paying for this drug, and therefore so are we, indirectly. Who do you think should be responsible for determining the proper dose?

Merck Settles Vioxx Lawsuits

The news media are reporting this morning that Merck has agreed to settle 27,000 lawsuits against the company for damages related to its painkiller, Vioxx, for $4.85 billion dollars. (See the New York Times online at nytimes.com, Nov. 9 - "Merck Agrees to Settle Vioxx Suits for $4.85 Billion"). Since the lawsuits cover about 47,000 plaintiffs, the average plaintiff will get around $100,000 before paying his/her lawyers 30-50%.

The issue of what Merck knew and when they knew it regarding the potential health damage that could be caused by Vioxx is highlighted in Human Biology 5th ed., pp. 182-183. Merck had vowed to fight each and every lawsuit over Vioxx in court, a strategy that seemed to work for the company. Because Merck won most of the first 20 cases, plaintiffs began to realize that their best hope was for a modest but guaranteed settlement, rather than the chance of nothing at all if they sued individually for huge amounts.

For Merck, $4.85 billion was less than Wall Street had anticipated, and less than one year’s profit.

Merck Avoids a Class-Action Lawsuit Over Vioxx

Yesterday the New Jersey Supreme Court rejected a class-action lawsuit brought against Merck by a union health plan. The International Union of Operating Engineers Local 68 in Caldwell, N.J. was seeking a class-action lawsuit representing all of the insurance companies nationwide that had ever paid for Vioxx prescriptions as part of their health care plans. The court ruled that a single nationwide class-action lawsuit was not appropriate under the circumstances. Each insurance company will now have to sue Merck on their own (or not).

The ruling is a victory for Merck. However, Merck still faces an estimated 27,000 lawsuits from individual patients who claim that Vioxx causes strokes and heart attacks, and that the company knew it long before the drug was pulled from the market. Merck has vowed to fight each and every lawsuit one at a time. So far the strategy is working – Merck has won nine and lost five. At this rate, most of the patients will be dead from other causes long before they ever see a dime from Merck.

By the way, remember Mr. Leonell Garza, the 71-year-old man described in the Current Issue feature in Human Biology, 5th ed. (pp. 182-183) whose family was suing Merck for $1 billion in damages? A Texas jury awarded the family $32 million, but that had to be reduced to $7.75 million by Texas law. Merck is appealing. Stay tuned!