Skip to Navigation
University of Pittsburgh
Print This Page Print this pages

June 22, 2006

Mini-medical school discusses pharmaceuticals

Fifteen years and $900 million. On average, that’s what it takes to get a new drug from the laboratory to consumers.

Why is it so expensive? And does it take too long for the federal Food and Drug Administration (FDA) to approve a drug for public use?

Those questions were at the heart of the argument at “When Good Drugs Go Bad,” the fifth presentation at the mini-medical school 2006 lecture/discussion series sponsored by Pitt’s School of Medicine.

The answer to the first question is that it is expensive by necessity, according to Barry I. Gold. The answer to the second question is relative. “If the drug turns out to be safe and effective, it took too long. If, on the other hand, the drug turns out to have serious side effects, it didn’t take long enough,” said Gold, who is professor and chair of the Department of Pharmaceutical Sciences at Pitt’s School of Pharmacy.

He, along with John S. Lazo, Allegheny Foundation Professor in the Department of Pharmacology at Pitt’s medical school and director of the newly formed Drug Discovery Institute (DDI), led the June 13 mini-medical school discussion.

(For a related story on DDI, see April 27 University Times.)

Lazo reviewed the drug discovery (pre-clinical) phase, where compounds are synthesized and tested via computer models and animal experiments — a process that can take up to 10 years.

But all of the work is necessary, Lazo maintained, because it is considered unethical to take a substance and give it to a person without having evaluated it for toxicity. Almost all drugs work by killing targeted cells, so they are, by definition, toxic. What pre-clinical testing attempts to establish through animal experiments is what other effects a particular drug may have, he said.

“It’s not a very efficient process when, after establishing a target, you start with up to 200,000 compounds and whittle that down to about 50 that you concentrate on during pre-clinical laboratory and animal testing,” Lazo said. “It takes years.”

Gold spoke on the drug development phase, that is, moving a compound out of the lab, testing it through a series of human clinical trials and garnering FDA approval. That process typically takes up to an additional 10 years.

They focused their presentation on three drugs, aspirin (discovered in 1899); thalidomide, which had disastrous results in the 1950s, and Vioxx, a drug approved by the FDA in 1989 but pulled off the shelves in 2004 for potential harmful side effects.

Both scientists acknowledged that the drug approval process is never infallible and, in the interest of safety and efficacy, the process is inefficient and, consequently, very expensive.

The researchers said that accounts in part for the pharmaceutical industry’s high risk, high reward scenario.

“Drugs are expensive to develop and test, so pharmaceutical companies focus on developing the ‘blockbuster’ drugs, those that can earn them billions a year,” Lazo said. “If, after all the testing, a new compound doesn’t work, the company essentially has wasted millions.”

Drug development also is an inexact process due to the variations, however slight, in human genes, human lifestyle differences that could affect medication reactions, range of patient toxicity tolerance and other hurdles, but especially that animal models are not always predictive of success in human beings, Lazo said.

The two most important sources of new drugs are natural products and compounds formed using combinatorial chemistry, Lazo said.

The first of several pre-clinical hurdles is the sheer volume of sources for possible medications, which has grown exponentially as pharmaceutical science has developed, he said.

“You may be surprised to know that even in the day of DNA knowledge more than half of all the drugs that we take are based on compounds taken directly from Mother Nature, such as codeine and morphine, or inspired by her,” Lazo said. Moreover, more than half of all the antibiotics in use are derived from bacteria. “Yet there are some 3 million species of bacteria yet to be explored for possible antibiotics,” as well as millions of marine organisms and plants that remain untested, he said.

The number of possible synthetic compounds that can be generated through combinatorial chemistry is even more staggering, he said. “I’ve been told by people who study this that there are a thousand million billion billion billion possible compounds in what we call ‘chemical space.’ That’s a 1 with at least 40 zeros after it,” Lazo said.

For this discussion, “My two drug ‘protagonists’ are aspirin and Vioxx,” he said. “Aspirin is a natural product that was first marketed in 1899. It’s still the world’s best selling drug, with 100 billion tablets sold a year.”

But its discovery was based purely on serendipitous observation, and, remarkably, it wasn’t until some 70 years later that scientists were able to figure out how it worked, he added.

Serendipity over time has given way to advances in human, cell and molecular biology and chemistry, Lazo said. “Today the focus is on genomics, proteomics and integrated biology, which has led to some cancer therapies and auto-immune disease therapies,” he said.

But despite the rigorous testing standards in place today, Vioxx is an example of a good drug gone bad, and now it is the subject of numerous lawsuits, Lazo said. “Some 80 million people took Vioxx or one of the drugs among the so-called ‘Cox-2 inhibitors,’” that is, anti-inflammatory drugs thought to improve on traditional drugs because they were believed to cause less stomach irritation and perforation, he said.

They are called Cox-2 inhibitors because they block an enzyme called cyclooxygenase, which is thought to trigger pain and inflammation in the body.

Vioxx was approved by the FDA in 1989, following a Phase III clinical trial of 5,435 patients.

But about 10 years after FDA approval, some research indicated that Vioxx also appeared to suppress prostacyclin, a substance that dilates blood vessels and reduces blood-clotting. By blocking pain and inflammation caused by cyclooxygenase, the Cox-2 inhibitor simultaneously may inhibit mechanisms that keep blood clots under control, potentially leading to heart attacks or other cardiovascular problems.

“The root of the problem is that it’s not clear even today through which mechanism Cox-2 inhibitors affect the cardiovascular system or what type of individual may be susceptible to side effects,” Lazo said.

Gold said that this illustrated the researcher’s dilemma. “Even in a large-scale clinical trial, when side effects are extremely rare they only become evident when a large number of people take the drug,” he said. “If the rate of adverse effects is one in a thousand, the effect will not show up in many clinical trials due to the limited size of the study group.”

But in the case of Vioxx and its companion drugs, 1 per 1,000 adverse effects over a sample of 80 million is 80,000.

“You can never measure completely how an individual’s genetic make-up will affect a drug. So, in every case, you must weigh the risks versus the benefits,” Gold said. “If you have serious side effects for a sleep aid, it may not be worth it, but serious side effects for a patient suffering from cancer may well be worth it.”

The approval process, therefore, is necessarily long and drawn out, even while it remains imperfect, he said. “There is strict adherence to scientific and ethical principles throughout the approval process,” which for clinical trials includes protocol approval from institutional review boards and several stages of increasingly larger human trials and follow-ups prior to FDA approval, Gold added.

“Most drugs interact with a number of cellular targets due to imperfect specificity,” Gold said. “Some targets are desired and some not. The goal is to tailor drugs to a specific disease or condition,” but unexpected outcomes can occur, he said.

Gold then offered an example of the flip-side, that is, when a bad drug “goes good.”

In the 1950s, thalidomide initially was tested as an antihistamine for allergy treatment, Gold said. “As testing proceeded, [researchers] discovered that it had no such properties. However, the trials indicated that it was an effective sleep aid. In particular, those targeted for use were people with nausea, and morning sickness during pregnancy.”

By 1958 thalidomide went into general use and became the drug of choice for pregnant women. It was marketed and prescribed around the world — except in the United States, where an unconvinced FDA withheld approvals.

What only belatedly was discovered was that thalidomide molecules could cross the placental wall and affect the fetus, causing blindness, deafness, disfigurement, internal disabilities or even death, Gold said. “This did not occur in any of the animal models used in pre-clinical studies,” he said.

Despite such a troubled history, thalidomide and its analogs are making a comeback. “Thalidomide can inhibit the growth of HIV in lab experiments,” Gold said. “In a small trial it was found to help with severe weight loss in people with AIDS, and trials have also shown that thalidomide can treat mouth ulcers in people with AIDS. It may be useful [for treating] severe rheumatoid arthritis.”

Sometimes, however, clinical trials reveal side effects that are beneficial. For example, the pharmaceutical company, Pfizer, was developing a compound that might act as an anti-hypertensive and anti-anginal drug. “Studies were done to see what side effects would come from increased dosages,” Gold said. “Volunteers in clinical trials reported back with side effects like headaches, visual problems and —” (he paused for dramatic effect:) “— prolongment of penile erections.”

The result: Viagra was born.

—Peter Hart


Leave a Reply