I'm just a pill. Yes, I'm just a pill. And I'm sitting here ...
Oh, hi. My name is Nupil. I'm a new drug, or at least I hope to be. Right now, the FDA is deciding whether to approve me. See that big office building? That's the Center for Drug Evaluation and Research. It's as important as it sounds. The fate of all new medicines that want to be sold in the U.S. is decided here.
Inside, FDA reviewers are carefully examining all the information that's known about me and talking it over together. They sure are busy. There are more than 100,000 pages of data, and it will take a team of reviewers several months to review. I guess I'll just have to sit here and be patient.
How did I end up here? Why, I'm glad you asked. That's an interesting story.
A Molecule Stands Out
About 12 years ago, I started out as a molecule, one of thousands researchers created in a laboratory. The scientists screened us, one by one, looking for some special properties. I was added to some cells in a test tube to see what I would do.
It was a long time ago, but I remember I liked almost everything about those cells, except for one awful little enzyme -- an enzyme that could make people sick. That enzyme really annoyed me, so I blocked its production, but left everything else alone. Well, the scientists were plenty pleased. I only did what came naturally to me, but now I know it was exactly what they were hoping for.
I didn't have a name yet, just a number: ABCD-523.
The Testing Begins
The scientists then started testing me in laboratory rats. The purpose of this was to see if I did the same thing in live animals that I did in the test tube. They also wanted to know if I had any toxic effects. They measured how I was absorbed and passed though the animal's body.
As Alan Goldhammer, PhD, associate vice president of regulatory affairs for the Pharmaceutical Research and Manufacturers of America (PhRMA), told me, "It's easy to identify lots of things that work inside a test tube." The challenge is finding something that works in a living body.
The results of the experiments were good. It's pretty rare for that to happen. Only one in 50 promising compounds will pass these tests. The vast majority don't work as expected, or they prove to be too toxic.
Meanwhile, researchers studied how I could be made into a pill. They wanted to make sure I wasn't too fragile -- that I could exist within a wide range of temperatures without degrading. They also looked at how difficult it would be to manufacture me on a large scale. It seems I'm not fussy about the weather, and I'm not impractical to make in bulk.
Many Hurdles to Clear
I had been through a lot of experiments already, but I still had a long way to go. To move to the next step, the drug maker sponsoring me needed the FDA to approve tests in humans. The company showed the FDA how well I performed in the animal tests and explained how they would study me in people, in what's called a phase I clinical trial.
With a thumbs-up from the FDA, the researchers started looking for people to try me. They needed 20-100 healthy volunteers. The purpose of the study was not to see if I worked, but rather to test my safety and side effects in humans.
Some people had mild side effects, like headaches and upset stomachs. Hey -- no one's perfect! I'll bet you've given someone a headache before. The fact is, all drugs cause side effects sometimes. But I didn't cause any serious problems for the people in this study.
I Got a Name
I got my "nonproprietary" name around this time: noperalate. That's my generic chemical name, the one scientists use when they're talking about me. It's different from my brand name, which was given later by the companies that will sell me. A group called the United States Adopted Names Council assigns generic names to new pharmaceutical compounds. I never thought WBMD-523 was really me, so I was happy to be called noperalate.
So far, so good. But in the next step, a phase II trial, I had to prove that I worked. Up to this point, I only had to show that I was likely to work. Now I had to perform. The researchers wanted to see that I could inhibit that enzyme reliably, in a larger number of people -- around 100 to 500 -- without harming them. I would also be compared to a placebo, that is, to a dummy pill. The researchers and test subjects wouldn't know who took me and who took the placebo until after the study was done.
Seven years had passed since I was first noticed in the lab and chosen for development. A lot of time, brainpower, and money had been invested in me, but there was still a chance I might fail. Clinical trials are kind of like the Olympics. Often very promising athletes make it to the games but ultimately don't measure up. About four out of five drugs don't make it through clinical trials.
Not everyone was cheering me on, either. Many scientists in the field were skeptical. They thought the early study results weren't convincing. By the time the phase II studies wrapped up, however, a lot of people were getting excited. It was clear I would go on to phase III.
The final phase of clinical trials lasted four years. I had to be tested on thousands of people, and show beyond a doubt that I really worked and that my benefits far outweighed any potential problems.
So, that brings us up to date. A few days ago, my sponsor filed a "new drug application" with the FDA. That's a formal request for the FDA to review a drug.
Like I said before, the drug company had to turn over every bit of information it had on me. That includes data from all the test-tube experiments, animal studies, and all the clinical trials.
I was curious about how the review process works, so I asked Sandra Kweder, MD, deputy director of the FDA's Office of New Drugs.
The FDA has many different experts on staff to review various parts of the application. They look at all aspects of it, not just the study data.
"For example, there will be a chemist who is reviewing the entire manufacturing and quality control system," Kweder explains.
Other ingredients will be mixed with me to make pills. Those ingredients have to be safe, too, and they can't react with me in a way that changes how I work.
Then there are the other experts:
They're all looking for problems with the evidence my sponsor submitted. They sometimes ask for more data, for example, from a study done over a longer time or one that includes more test subjects. I'm confident we have given the reviewers all they need, though. My sponsor has kept in touch with the FDA throughout the clinical trials, and even asked how to design studies to best meet the FDA's requirements.
The reviewers don't have to rely entirely on the sponsor's interpretation of the data, either. Because they have access to all the study data, they can do their own analysis if they see fit.
"That is what makes the U.S. review system so unique," Kweder says. "No other countries do that."
The application also includes proposed label information: instructions on how to use me, what I'm supposed to do, and what side effects and safety issues I have. Often the FDA wants to tweak what will be printed on the label.
In some cases, but not mine, the FDA will convene an advisory committee. Clinical trials may reveal that there are serious risks to be balanced with the drug's benefits, or there may be doubt about whether the drug really works. "Even before the application comes in, we have some sense of what the studies show, and we know that this is going to be a close call," Kweder says. "Those close calls are a common reason to take something to an advisory committee."
An advisory committee may also be useful if a drug is controversial, or if it's so new that nothing like it has ever been approved before. The committee is made up of independent experts. Its recommendations are weighed seriously, but the FDA is not legally required to follow them.
Finally, every reviewer will write a report. A top official will consider the reviewers' recommendations and make a decision: "approved," "approvable," or "not approvable."
An approved drug has a green light to be marketed that very day. For an "approvable" drug, final approval may depend on the drug maker meeting certain conditions, such as providing additional data. A drug that's "not approvable" is essentially shot down.
In 2003, it took the FDA about 17 months, on average, to finish a review. But some drugs get a priority review. That's when there is an urgent need for it to reach patients as soon as possible. Many drugs developed to treat AIDS had priority reviews, for example. "For priority reviews, we have a six-month review clock," Kweder says.
The FDA also has to approve a drug's brand name, which the drug maker invents. A brand name can't be misleading, self-promoting, or too similar to an existing drug name. A name like "Curezital," or "Lipitar" would never be allowed.
If I'm approved, I'll be sold as Nupil® (noperalate).
I'm really excited for that day. Hopefully I won't have too long to wait. The drug maker's factories are poised to swing into production; ad campaigns are prepared; and legions of salesmen are ready to fan out across the country as soon as the approval letter arrives.
The Rest of the Story
There's one last thing I want to mention before you go. My story won't necessarily end with approval and marketing. The drug maker and other researchers will keep on studying me. Someone may see a new use for me, in which case I'll have to go through the approval process again to be marketed for that use. For instance, drugs first developed to treat a certain kind of cancercancer have later been put to different uses. "There are many cases in the development of cancer drugs where companies will be studying new indications throughout the life cycle of the drug," PhRMA's Goldhammer says.
Of course, you also know that several drugs have been pulled off the market recently because of safety problems. Others have had special warnings added to their labels. Constant testing and careful attention to reports from doctors and consumers using prescription drugs sometimes uncovers problems that can't be ignored.
Nevertheless, I believe I'll end up helping millions of people for many years, until a better treatment comes along to replace me.
Wish me luck!